[6,6] and [6,7]-bicyclic gpr119 g protein-coupled receptor agonists

ABSTRACT

Novel compounds are provided which are GPR119 G protein-coupled receptor modulators. GPR119 G protein-coupled receptor modulators are useful in treating, preventing, or slowing the progression of diseases requiring GPR119 G protein-coupled receptor modulator therapy. These novel compounds have the structure: 
     
       
         
         
             
             
         
       
     
     or stereoisomers or prodrugs or pharmaceutically acceptable salts thereof, wherein n 1 , n 2 , n 3 , n 4 , A, B, D, E, G, Y, Z, R 1  and R 2  are defined herein.

RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.13/289,375, filed Nov. 4, 2011, now allowed, which claims prioritybenefit of U.S. patent application Ser. No. 13/022,819, filed Feb. 8,2011, issued as U.S. Pat. No. 8,076,322 B2, which claims prioritybenefit of U.S. patent application Ser. No. 12/112,080, filed Apr. 30,2008, issued as U.S. Pat. No. 7,910,583 B2, which claims prioritybenefit of U.S. Provisional Application No. 60/915,944, filed on May 4,2007. The entirety of each of these applications is incorporated hereinby reference.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a serious disease afflicting over 100 millionpeople worldwide. In the United States, there are more than 12 milliondiabetics, with 600,000 new cases diagnosed each year. Diabetes mellitusis a diagnostic term for a group of disorders characterized by abnormalglucose homeostasis resulting in elevated blood sugar. There are manytypes of diabetes, but the two most common are Type 1 (also referred toas insulin-dependent diabetes mellitus or IDDM) and Type 2 (alsoreferred to as non-insulin-dependent diabetes mellitus or NIDDM).

The etiology of the different types of diabetes is not the same;however, everyone with diabetes has two things in common: overproductionof glucose by the liver and little or no ability to move glucose out ofthe blood into the cells where it becomes the body's primary fuel.

People who do not have diabetes rely on insulin, a hormone made in thepancreas, to move glucose from the blood into the cells of the body.However, people who have diabetes either do not produce insulin orcannot efficiently use the insulin they produce; therefore, they cannotmove glucose into their cells. Glucose accumulates in the blood creatinga condition called hyperglycemia, and over time, can cause serioushealth problems.

Diabetes is a syndrome with interrelated metabolic, vascular, andneuropathic components. The metabolic syndrome, generally characterizedby hyperglycemia, comprises alterations in carbohydrate, fat and proteinmetabolism caused by absent or markedly reduced insulin secretion and/orineffective insulin action. The vascular syndrome consists ofabnormalities in the blood vessels leading to cardiovascular, retinaland renal complications. Abnormalities in the peripheral and autonomicnervous systems are also part of the diabetic syndrome.

Diabetes has also been implicated in the development of kidney disease,eye diseases and nervous-system problems. Kidney disease, also callednephropathy, occurs when the kidney's “filter mechanism” is damaged andprotein leaks into urine in excessive amounts and eventually the kidneyfails. Diabetes is also a leading cause of damage to the retina at theback of the eye and increases risk of cataracts and glaucoma. Finally,diabetes is associated with nerve damage, especially in the legs andfeet, which interferes with the ability to sense pain and contributes toserious infections. Taken together, diabetes complications are one ofthe nation's leading causes of death.

Many people with NIDDM have sedentary lifestyles and are obese; theyweigh approximately 20% more than the recommended weight for theirheight and build. Furthermore, obesity is characterized byhyperinsulinemia and insulin resistance, a feature shared with NIDDM,hypertension and atherosclerosis.

Obesity, which is the result of an imbalance between caloric intake andenergy expenditure, is highly correlated with insulin resistance anddiabetes in experimental animals and human. However, the molecularmechanisms that are involved in obesity-diabetes syndromes are notclear. During early development of obesity, increased insulin secretionbalances insulin resistance and protects patients from hyperglycemia (LeStunff et al., Diabetes, 43:696-702 (1989)). However, over time, β-cellfunction deteriorates and non-insulin-dependent diabetes develops inabout 20% of the obese population (Pederson, P., Diab. Metab. Rev.,5:505-509 (1989) and Brancati, F. L. et al., Arch. Intern. Med.,159:957-963 (1999)). Given its high prevalence in modern societies,obesity has thus become the leading risk factor for NIDDM (Hill, J. O.et al., Science, 280:1371-1374 (1998)). However, the factors whichpredispose a fraction of patients to alteration of insulin secretion inresponse to fat accumulation remain unknown. The most common diseaseswith obesity are cardiovascular disease (particularly hypertension),diabetes (obesity aggravates the development of diabetes), gall bladderdisease (particularly cancer) and diseases of reproduction. Research hasshown that even a modest reduction in body weight can correspond to asignificant reduction in the risk of developing coronary heart disease.

Obesity considerably increases the risk of developing cardiovasculardiseases as well. Coronary insufficiency, atheromatous disease, andcardiac insufficiency are at the forefront of the cardiovascularcomplication induced by obesity. It is estimated that if the entirepopulation had an ideal weight, the risk of coronary insufficiency woulddecrease by 25% and the risk of cardiac insufficiency and of cerebralvascular accidents by 35%. The incidence of coronary diseases is doubledin subjects less than 50 years of age who are 30% overweight. Thediabetes patient faces a 30% reduced lifespan. After age 45, people withdiabetes are about three times more likely than people without diabetesto have significant heart disease and up to five times more likely tohave a stroke. These findings emphasize the inter-relations betweenrisks factors for NIDDM, obesity and coronary heart disease as well asthe potential value of an integrated approach involving the treatment ofboth obesity and diabetes (Perry, I. J. et al., BMJ, 310:560-564(1995)).

Type 2 diabetes results from the progressive loss of pancreatic β-cellfunction in the presence of insulin resistance, leading to an overallreduction in insulin output (Prentki, M. et al., “Islet failure in type2 diabetes”, J. Clin. Invest., 116:1802-1812 (2006)). β-cells are thecell type that store and release insulin in response to an elevation inplasma glucose or in response to hormonal signals from the gut followingthe ingestion of food. Evidence suggests that in type 2 diabetics therate of β-cell cell death (apoptosis) exceeds that of new β-celldevelopment, yielding an overall loss in β-cell number (Butler, A. E. etal., “β-cell deficit and increased β-cell apoptosis in humans with type2 diabetes”, Diabetes, 52:102-110 (2003)). β-cell apoptosis may arisefrom persistent elevations in plasma glucose levels (glucotoxicity)and/or plasma lipid levels (lipotoxicity).

G-protein coupled receptors (GPCRs) expressed on β-cells are known tomodulate the release of insulin in response to changes in plasma glucoselevels (Ahren, B., “Autonomic regulation of islet hormonesecretion—Implications for health and disease”, Diabetologia, 43:393-410(2003)). Those GPCRs specifically coupled to the elevation of cAMP viathe G_(s) alpha subunit of G-protein, have been shown to enhanceglucose-stimulated insulin release from β-cells. Cyclic AMP-stimulatingGPCRs on β-cells include the GLP-1, GIP, β2-adrenergic receptors andGPR119. Increasing cAMP concentration in β-cells is known to lead to theactivation of PKA which is thought to prevent the opening of potassiumchannels on the surface of the β-cell. The reduction in K⁺ effluxdepolarizes the β-cell leading to an influx of Ca⁺⁺ which promotes therelease of insulin.

GPR119 (e.g., human GPR119, GenBank® Accession No. AAP72125 and allelesthereof; e.g., mouse GPR119, GenBank® Accession No. AY288423 and allelesthereof) is a GPCR located at chromosome position Xp26.1 (Fredricksson,R. et al., “Seven evolutionarily conserved human rhodopsin Gprotein-coupled receptors lacking close relatives”, FEBS Lett.,554:381-388 (2003)). The receptor is coupled to Gs, and when stimulated,produces an elevation in cAMP in a variety of cell types includingβ-cell-derived insulinomas (Soga, T. et al., “Lysophosphatidylcholineenhances glucose-dependent insulin secretion via an orphanG-protein-coupled receptor”, Biochem. Biophys. Res. Comm., 326:744-751(2005), International Applications WO 04/065380, WO 04/076413, WO05/007647, WO 05/007658, WO 05/121121, WO 06/083491, and EP 1338651).The receptor has been shown to be localized to the β-cells of thepancreas in a number of species as well as in specific cell types of thegastrointestinal tract. Activation of GPR119, with agonist ligands suchas lysophosphatidylcholine, produce a glucose dependent increase ininsulin secretion from primary mouse islets and various insulinoma celllines such as NIT-1 and HIT-T15 (Soga, T. et al.,“Lysophosphatidylcholine enhances glucose-dependent insulin secretionvia an orphan G-protein-coupled receptor”, Biochem. Biophys. Res. Comm.,326:744-751 (2005); Chu, Z. L. et al., “A role for β-cell-expressedGPR119 in glycemic control by enhancing glucose-dependent insulinrelease”, Endocrinology(2007) doi:10.1210/en.2006-1608).

When activators of GPR119 are administered to either normal mice or micethat are prone to diabetes due to genetic mutation, prior to an oralglucose tolerance test, improvements in glucose tolerance are observed.A short-lived increase in plasma glucagon-like peptide-1 and plasmainsulin levels are also observed in these treated animals (Chu, Z. L. etal., “A role for β-cell-expressed GPR119 in glycemic control byenhancing glucose-dependent insulin release”, Endocrinology(2007)doi:10.1210/en.2006-1608). In addition to effects on plasma glucoselevels, GPR119 activators have also been demonstrated to producereductions in acute food intake and to reduce body weight in ratsfollowing chronic administration (Overton, H. A. et al.,“Deorphanization of a G protein-coupled receptor for oleoylethanolamideand its use in the discovery of small-molecule hypophagic agents”, CellMetabolism, 3:167-175 (2006), WO 05/007647, WO 05/007658).

SUMMARY OF THE INVENTION

In accordance with the present invention, aryl and heterocyclyl andrelated compounds are provided that have the general structure offormula I:

wherein n₁, n₂, n₃, n₄, A, B, D, E, G, Y, Z, R₁ and R₂ are definedbelow.

Compounds of the present invention modulate the activity of Gprotein-coupled receptors. Preferably, compounds of the presentinvention modulate the activity of the GPR119 G protein-coupled receptor(“GPR119”). Consequently, the compounds of the present invention may beused in the treatment of multiple diseases or disorders associated withGPR119, such as diabetes and related conditions, microvascularcomplications associated with diabetes, the macrovascular complicationsassociated with diabetes, cardiovascular diseases, Metabolic Syndromeand its component conditions, obesity and other maladies. Examples ofdiseases or disorders associated with the modulation of the GPR119 Gprotein-coupled receptor that can be prevented, modulated, or treatedaccording to the present invention include, but are not limited to,diabetes, hyperglycemia, impaired glucose tolerance, insulin resistance,hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed woundhealing, atherosclerosis and its sequelae, abnormal heart function,myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity,dislipidemia, dylsipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia,infection, cancer, vascular restenosis, pancreatitis, neurodegenerativedisease, lipid disorders, cognitive impairment and dementia, bonedisease, HIV protease associated lipodystrophy and glaucoma. In general,tested compounds of the instant invention show GPR119 functionalactivity with an EC_(5O) of <10 μM.

The present invention provides compounds of Formula I, pharmaceuticalcompositions employing such compounds, and methods of using suchcompounds. In particular, the present invention provides apharmaceutical composition comprising a therapeutically effective amountof a compound of Formula I, alone or in combination with apharmaceutically acceptable carrier.

Further, in accordance with the present invention, a method is providedfor preventing, modulating, or treating the progression or onset ofdiseases or disorders associated with the activity of the GPR119 Gprotein-coupled receptor, such as defined above and hereinafter, whereina therapeutically effective amount of a compound of Formula I isadministered to a mammalian, i.e., human, patient in need of treatment.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s).

Further, the present invention provides a method for preventing,modulating, or treating the diseases as defined above and hereinafter,wherein a therapeutically effective amount of a combination of acompound of Formula I and another compound of Formula I and/or at leastone other type of therapeutic agent, is administered to a mammalian,i.e., human, patient in need of treatment.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, compounds of Formula I areprovided:

as well as enantiomers, stereoisomers (such as diastereomers), solvates,and salts (particularly pharmaceutically acceptable salts) thereofwherein:

A, B and D are each independently selected to be CR_(4b) or N;

E is CH₂, O or NH, provided that when E is CH₂ at least one of A, B or Dis N;

G is CH or N;

Y is —NR₃, O or S;

Z is absent or ═O;

n₁ is 1 or 2;

n₂ and n₃ are each independently selected to be 0-2;

n₄ is 0-3;

R₁ is aryl or heteroaryl, each of which may optionally be substitutedwith one or more substituents selected from R₄ (more particularly 1-5 ofR₄);

R₂ is selected from the group consisting of cycloalkyl, aryl,heteroaryl, heterocyclyl, —C(═O)R₅ and —C(═O)OR₅, wherein thecycloalkyl, aryl, heteroaryl and heterocyclyl may each be optionallysubstituted with one or more R₆'s (particularly 1-5) R₆'s;

R₃ is selected from the group consisting of hydrogen, alkyl, alkoxy,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl (particularly wherein the heteroaryl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl each contain 1-4heteroatoms selected from N, O and S);

R₄, at each occurrence, is independently selected from the groupconsisting of alkyl, aryl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heterocyclyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀,—OH, —SH, —SR₁₀, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉,—NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀,—OC(═O)NR₉R₉, —C(═NR₁₄)NR₉R₉, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀,—NR₉C(═O)OR₈ and —NR₉S(O₂)R₈, wherein the alkyl, aryl, alkenyl, alkynyl,cycloalkyl, heteroaryl and heterocyclyl may each be optionallysubstituted with one or more R₆'s (particularly 1-5 R₆'s);

R_(4b), at each occurrence, is independently selected from the groupconsisting of hydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl,cycloalkyl, heteroaryl, heterocyclyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —S(O)₃H, —P(O)₃H₂,—C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉,—S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀,—NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀, —OC(═O)NR₉R₉, —C(═NR₁₄)NR₉R₉,—NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈ and —NR₉S(O₂)R₈,wherein the alkyl, aryl, alkenyl, alkynyl, cycloalkyl, heteroaryl andheterocyclyl may each be optionally substituted with one or more R₆'s(particularly 1-5 R₆'s);

R₅ is selected from the group consisting of alkyl, aryl, cycloalkyl,heteroaryl and heterocyclyl, each of which may optionally be substitutedwith one or more R₆'s (particularly 1-5 R₆'s);

R₆, at each occurrence, is independently selected from the groupconsisting of alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclylheterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OCF₃,—OR₁₀, —OH, —SH, —SR₁₀, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)H,—NR₉C(═O)R₁₀, —OC(═O)R₁₀, —C(═NR₁₄)NR₉R₉, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀,—S(O)₂R₁₀, —NR₉C(═O)OR₈ and —NR₉S(O₂)R₈;

R₈, at each occurrence, is independently selected from the groupconsisting of alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl;

R₉, at each occurrence, is independently selected from the groupconsisting of hydrogen, alkyl, alkoxy, cycloalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, whereinthe aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl orheterocyclylalkyl may each be optionally substituted with 0-5 R_(9a),and the heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyleach contain 1-4 heteroatoms selected from N, O and S;

R_(9a), at each occurrence, is independently selected from the groupconsisting of alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclylheterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄, —OH, —SH, —SR₁₄, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)H,—NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —C(═NR₁₄)NR₁₄R₁₄, —NHC(═NR₁₄)NR₁₄R₁₄,—S(═O)R₁₄, —S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ and arylalkyl;

R₁₀, at each occurrence, is independently selected from the groupconsisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, whereinthe aryl, arylalkyl, heterocyclyl and heterocyclylalkyl may each beoptionally substituted with 0-5 R_(10a), and the heterocyclyl andheterocyclylalkyl each contain 1-4 heteroatoms selected from N, O and S;

R_(10a), at each occurrence, is independently selected from the groupconsisting of alkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclylheterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄, —OH, —SH, —SR₁₄, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄,—S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃, —C(═O)NR₁₄S(O)₂R₉, —S(O)₂NR₁₄C(═O)OR₉,—S(O)₂NR₁₄C(═O)NR₁₄R₁₄, —C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)H,—NR₁₄C(═O)R₁₄, —OC(═O)R₁₄, —C(═NR₁₄)NR₁₄R₁₄, —NHC(═NR₁₄)NR₁₄R₁₄,—S(═O)R₁₄, —S(O)₂R₁₄, —NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ and arylalkyl; and

R₁₄, at each occurrence, is independently selected from the groupconsisting of hydrogen, alkyl, cycloalkyl and aryl.

In a first particular embodiment, compounds of Formula I are providedwherein A and D are each independently CR_(4b) or N, and B is CH.

In a second particular embodiment, compounds of Formula I are providedwherein A and D are each independently CR_(4b) or N, B is CH, and E is Oor NH.

In a third particular embodiment, compounds of Formula I are providedwherein A, B and D are each CR_(4b).

In a fourth particular embodiment, compounds of Formula I are providedwherein A, B and D are each CR_(4b), and E is O or NH.

In a fifth particular embodiment, compounds of Formula I are providedwherein A and D are each N, and B is CR_(4b).

In a sixth particular embodiment, compounds of Formula I are providedwherein A and D are each N, B is CR_(4b), and E is O or NH.

In a seventh particular embodiment, compounds of Formula I are providedwherein A is N, and B and D are each CR_(4b).

In an eighth particular embodiment, compounds of formula I are providedwherein A is N, B and D are each CR_(4b), and E is O or NH.

In a ninth particular embodiment, compounds of Formula I are providedwherein R_(4b) is H.

In a tenth particular embodiment, compounds of formula I are providedwherein:

Y is —NR₃, O or S;

Z is absent or ═O;

n₁ is 1 or 2;

n₂ and n₃ are each independently 1 or 2;

n₄ is 0-3;

R₁ is aryl or heteroaryl, each of which may be optionally substitutedwith one or more substituents selected from R₄;

R₂ is selected from the group consisting of cycloalkyl, aryl,heteroaryl, heterocyclyl, —C(═O)R₅ and —C(═O)OR₅, wherein thecycloalkyl, aryl, heteroaryl and heterocyclyl may each be optionallysubstituted with one or more R₆'s;

R₃ is hydrogen, alkyl, or cycloalkyl;

R₄, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6 cycloalkyl,heteroaryl, heterocyclyl, halo, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀,—OH, —SR₁₀, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉,—NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀,—OC(═O)NR₉R₉, —C(═NR₁₄)NR₉R₉, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀,—NR₉C(═O)OR₈ and —NR₉S(O₂)R₈, wherein the alkyl, aryl, cycloalkyl,heteroaryl and heterocyclyl may each be optionally substituted with oneor more R₆'s;

R_(4b), at each occurrence, is independently selected from the groupconsisting of hydrogen, alkyl, haloalkyl, cycloalkyl, halo, CN, —OH,—OR₁₀, —SR₁₀, aryl, heteroaryl and heterocyclyl, wherein the alkyl,cycloalkyl, aryl, heteroaryl and heterocyclyl may each be optionallysubstituted with one or more R₆'s;

R₅ is selected from the group consisting of alkyl, aryl, cycloalkyl,heteroaryl and heterocyclyl, each of which may optionally be substitutedwith one or more R₆'s;

R₆, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6 cycloalkyl,heteroaryl, heterocyclyl, halo, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀,—OH, —SR₁₀, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉,—NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀,—C(═NR₁₄)NR₉R₉, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈and —NR₉S(O₂)R₈;

R₈, at each occurrence, is independently selected from the groupconsisting of alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl;

R₉, at each occurrence, is independently selected from the groupconsisting of hydrogen, C1-6 alkyl, C6-10 aryl, C3-6 cycloalkyl,heteroaryl and heterocyclyl, wherein the aryl, heteroaryl andheterocyclyl may optionally be substituted with 0-5 R_(9a), and theheteroaryl and heterocyclyl each contain 1-4 heteroatoms selected fromN, O and S;

R_(9a), at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6 cycloalkyl,heteroaryl, heterocyclyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄ and —OH;

R₁₀, at each occurrence, is independently selected from the groupconsisting of alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl,wherein the aryl, heteroaryl and heterocyclyl may each be optionallysubstituted with 0-5 R_(10a), and the heteroaryl and heterocyclyl eachcontains 1-4 heteroatoms selected from N, O and S;

R_(10a), at each occurrence, is independently selected from C1-6 alkyl,C1-4 haloalkyl, C6-10 aryl, C3-6 cycloalkyl, heteroaryl, heterocyclyl,halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄, and —OH; and

R₁₄, at each occurrence, is independently selected from hydrogen, C1-6alkyl, C3-6 cycloalkyl or C6-10 aryl.

In an eleventh particular embodiment, compounds of Formula I areprovided wherein:

Y is —NR₃, O or S;

Z is absent or ═O;

n₁ is 1 or 2;

n₂ and n₃ are each independently 1 or 2;

n₄ is 0-3;

R₁ is aryl or heteroaryl, each of which may be optionally substitutedwith one or more substituents selected from R₄;

R₂ is selected from the group consisting of aryl, heteroaryl,heterocyclyl, —C(═O)R₅ and —C(═O)OR₅, wherein the aryl, heteroaryl andheterocyclyl may each be optionally substituted with one or more R₆'s;

R₃ is hydrogen or alkyl;

R₄, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6 cycloalkyl,heteroaryl, heterocyclyl, halo, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀,—OH, —SR₁₀, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉,—NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀,—OC(═O)NR₉R₉, —C(═NR₁₄)NR₉R₉, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀,—NR₉C(═O)OR₈ and —NR₉S(O₂)R₈, wherein the alkyl, aryl, cycloalkyl,heteroaryl and heterocyclyl may each be optionally substituted with oneor more R₆'s;

R_(4b), at each occurrence, is independently selected from the groupconsisting of hydrogen, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6cycloalkyl, halo, CN, —OH, —OR₁₀ and —SR₁₀, wherein the alkyl,cycloalkyl, and aryl may each be optionally substituted with one or moreR₆'s;

R₅ is selected from the group consisting of C1-6 alkyl, C6-10 aryl, C3-6cycloalkyl, heteroaryl and heterocyclyl, each of which may optionally besubstituted with one or more R₆'s;

R₆, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6 cycloalkyl,heteroaryl, heterocyclyl, halo, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀,—OH, —SR₁₀, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉,—NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀,—C(═NR₁₄)NR₉R₉, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈and —NR₉S(O₂)R₈;

R₈, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C6-10 aryl, C3-6 cycloalkyl, heteroaryl andheterocyclyl;

R₉, at each occurrence, is independently selected from the groupconsisting of hydrogen, C1-6 alkyl, C6-10 aryl, C3-6 cycloalkyl,heteroaryl and heterocyclyl, wherein the aryl, heteroaryl andheterocyclyl may each be optionally substituted with 0-5 R_(9a), and theheteroaryl and heterocyclyl each contain 1-4 heteroatoms selected fromN, O and S;

R_(9a), at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄ and —OH;

R₁₀, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl, heteroaryl andheterocyclyl, wherein the aryl, heteroaryl and heterocyclyl may each beoptionally substituted with 0-5 R_(10a), and the heteroaryl andheterocyclyl each contains 1-4 heteroatoms selected from N, O and S;

R_(10a), at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄ and —OH; and

R₁₄, at each occurrence, is independently selected from the groupconsisting of hydrogen, C1-6 alkyl and C6-10 aryl.

In a twelfth particular embodiment, compounds of Formula I are providedwherein:

Y is —NR₃, O or S;

Z is absent or ═O;

n₁ is 1 or 2;

n₂ and n₃ are each independently 1 or 2;

n₄ is 0 or 2;

R₁ is C6-10 aryl or heteroaryl, each of which may optionally besubstituted with one or more substituents selected from R₄;

R₂ is selected from the group consisting of C6-10 aryl, heteroaryl,—C(═O)R₅ and —C(═O)OR₅, wherein the aryl and heteroaryl may each beoptionally substituted with one or more R₆'s;

R₃ is hydrogen or C1-4 alkyl;

R₄, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6 cycloalkyl,heteroaryl, heterocyclyl, halo, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀,—OH, —SR₁₀, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉,—NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀,—OC(═O)NR₉R₉, —C(═NR₁₄)NR₉R₉, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀,—NR₉C(═O)OR₈ and —NR₉S(O₂)R₈, wherein the alkyl, aryl, cycloalkyl,heteroaryl and heterocyclyl may each be optionally substituted with oneor more R₆'s;

R_(4b), at each occurrence, is independently selected from the groupconsisting of hydrogen, C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6cycloalkyl, halo, CN, —OH, —OR₁₀ and —SR₁₀, wherein the alkyl,cycloalkyl and aryl may each be optionally substituted with one or moreR₆'s;

R₅ is selected from the group consisting of C1-6 alkyl, C6-10 aryl, C3-6cycloalkyl and heteroaryl each of which may optionally be substitutedwith one or more R₆'s;

R₆, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6 cycloalkyl,heteroaryl, heterocyclyl, halo, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀,—OH, —SR₁₀, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉,—NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀,—C(═NR₁₄)NR₉R₉, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈and —NR₉S(O₂)R₈;

R₈, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C6-10 aryl, C3-6 cycloalkyl and heteroaryl;

R₉, at each occurrence, is independently selected from the groupconsisting of hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and orheteroaryl, wherein the aryl and heteroaryl may each be optionallysubstituted with 0-5 R_(9a), and the heteroaryl contains 1-4 heteroatomsselected from N, O and S;

R_(9a), at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄ and —OH;

R₁₀, at each occurrence, is independently selected from the groupconsisting of hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl andheteroaryl, wherein the aryl and heteroaryl may each be optionallysubstituted with 0-5 R_(10a), and the heteroaryl contains 1-4heteroatoms selected from N, O and S;

R_(10a), at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄ and —OH; and

R₁₄, at each occurrence, is independently selected from the groupconsisting of hydrogen, C1-6 alkyl and C6-10 aryl

In a thirteenth particular embodiment, compounds of Formula I areprovided wherein:

Y is —NR₃, O or S;

Z is absent or ═O;

n₁ is 1 or 2;

n₂ and n₃ are independently 1 or 2;

n₄ is 0 or 2;

R₁ is C6-10 aryl or heteroaryl, each of which may optionally besubstituted with one or more substituents selected from R₄;

R₂ is heteroaryl, —C(═O)R₅ or —C(═O)OR₅, wherein the heteroaryl may beoptionally substituted with one or more R₆'s;

R₃ is hydrogen;

R₄, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6 cycloalkyl,heteroaryl, heterocyclyl, halo, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OCF₃,—OR₁₀, —OH, —SH, —SR₁₀, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)H,—NR₉C(═O)R₁₀, —OC(═O)R₁₀, —OC(═O)NR₉R₉, —C(═NR₁₄)NR₉R₉,—NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈ and —NR₉S(O₂)R₈,wherein the alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl mayeach be optionally substituted with one or more R₆'s;

R_(4b), at each occurrence, is independently selected from the groupconsisting of hydrogen, C1-6 alkyl, C6-10 aryl and C3-6 cycloalkyl,wherein the alkyl, cycloalkyl, and aryl may each be optionallysubstituted with one or more R₆'s;

R₅ is selected from the group consisting of C1-6 alkyl, C6-10 aryl andC3-6 cycloalkyl, each of which may optionally be substituted with one ormore R₆'s;

R₆, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6 cycloalkyl,heteroaryl, heterocyclyl, halo, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OCF₃,—OR₁₀, —OH, —SH, —SR₁₀, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)H,—NR₉C(═O)R₁₀, —OC(═O)R₁₀, —C(═NR₁₄)NR₉R₉, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀,—S(O)₂R₁₀, —NR₉C(═O)OR₈ or —NR₉S(O₂)R₈;

R₈, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl and C6-10 aryl;

R₉, at each occurrence, is independently selected from the groupconsisting of hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl andheteroaryl, wherein the aryl and heteroaryl may each be optionallysubstituted with 0-5 R_(9a), and the heteroaryl contains 1-4 heteroatomsselected from N, O and S;

R_(9a), at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄ and —OH;

R₁₀, at each occurrence, is independently selected from the groupconsisting of hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl andheteroaryl, wherein the aryl and heteroaryl may each be optionallysubstituted with 0-5 R_(10a), and the heteroaryl contains 1-4heteroatoms selected from N, O and S;

R_(10a), at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄ and —OH; and

R₁₄, at each occurrence, is independently selected from the groupconsisting of hydrogen, C1-6 alkyl and C6-10 aryl.

In a fourteenth particular embodiment, compounds of Formula I areprovided wherein:

Y is —NR₃, O or S;

Z is absent or ═O;

n₁ is 1 or 2;

n₂ and n₃ are independently 1 or 2;

n₄ is 0;

R₁ is C6-10 aryl or heteroaryl, each of which may be optionallysubstituted with one or more substituents (for example, 1-5) of selectedfrom R₄;

R₂ is heteroaryl, —C(═O)R₅ or —C(═O)OR₅, wherein the heteroaryl may beoptionally substituted with one or more (for example, 1-5) of R₆'s;

R₃ is hydrogen;

R₄, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6 cycloalkyl,heteroaryl, heterocyclyl, halo, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀,—OH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —C(═O)NR₉S(O)₂R₉,—S(O)₂NR₉C(═O)OR₉, —C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)NR₉R₉,—S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈ and —NR₉S(O₂)R₈, wherein the alkyl,aryl, cycloalkyl, heteroaryl and heterocyclyl may be each optionallysubstituted with one or more R₆'s;

R_(4b), at each occurrence, is independently selected from the groupconsisting of hydrogen, C1-6 alkyl and C3-6 cycloalkyl, wherein thealkyl and cycloalkyl may each be optionally substituted with one or moreR₆'s;

R₅ is C1-6 alkyl, C6-10 aryl or C3-6 cycloalkyl, each of which may beoptionally substituted with one or more R₆'s;

R₆, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C6-10 aryl, C3-6 cycloalkyl, heteroaryl,heterocyclyl, halo, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SR₁₀,—C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)NR₉R₉, —S(═O)R₁₀, —S(O)₂R₁₀,—NR₉C(═O)OR₈ and —NR₉S(O₂)R₈;

R₈, at each occurrence, is independently C1-6 alkyl or C6-10 aryl;

R₉, at each occurrence, is independently selected from the groupconsisting of hydrogen, C1-6 alkyl, C3-6 cycloalkyl and C6-10 aryl,wherein the aryl may be optionally substituted with 0-5 R_(9a);

R_(9a), at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄ and —OH;

R₁₀, at each occurrence, is independently hydrogen, C1-6 alkyl, C3-6cycloalkyl or C6-10 aryl, wherein the aryl may optionally be substitutedwith 0-5 R_(10a);

R_(10a), at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄ and —OH; and

R₁₄, at each occurrence, is independently hydrogen, C1-6 alkyl or C6-10aryl.

In a fifteenth particular embodiment, compounds of Formula I areprovided wherein:

A and D are each independently CH or N;

B is CH;

E is O or NH;

G is CH or N;

Y is —NR₃ or O;

Z is absent or ═O;

n₁ is 1 or 2;

n₂ and n₃ are each 1;

n₄ is 0;

R₁ is phenyl or heteroaryl, each of which may optionally be substitutedwith one or more substituents (for example, 1-5) selected from R₄;

R₂ is heteroaryl, —C(═O)R₅ or —C(═O)OR₅, wherein the heteroaryl mayoptionally be substituted with one or more R₆'s;

R₃ is hydrogen;

R₄, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, phenyl,heteroaryl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH,—SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —C(═O)NR₉S(O)₂R₉,—S(O)₂NR₉C(═O)OR₉, —C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)NR₉R₉,—S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈ and —NR₉S(O₂)R₈, wherein the alkyl,phenyl, or heteroaryl may each be optionally substituted with one ormore (for example, 1-5) R₆'s;

R_(4b), at each occurrence, is independently hydrogen or C1-6 alkyl;

R₅ is C1-6 alkyl, C3-6 cycloalkyl or phenyl, each of which mayoptionally be substituted with one or more (for example, 1-5) R₆'s;

R₆, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C1-4 haloalkyl, phenyl, heteroaryl, halo,—NH₂, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —C(═O)R₁₀,—NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)NR₉R₉, —S(═O)R₁₀, —S(O)₂R₁₀,—NR₉C(═O)OR₈ and —NR₉S(O₂)R₈;

R₈, at each occurrence, is independently C1-6 alkyl or phenyl;

R₉, at each occurrence, is independently hydrogen, C1-6 alkyl, C3-6cycloalkyl or phenyl, wherein the phenyl may be optionally substitutedwith 0-5 R_(9a);

R_(9a), at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄ and —OH;

R₁₀, at each occurrence, is independently hydrogen, C1-6 alkyl, C3-6cycloalkyl or phenyl, wherein the phenyl may be optionally substitutedwith 0-5 R_(10a);

R_(10a), at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄ and —OH; and

R₁₄, at each occurrence, is independently hydrogen, C1-6 alkyl orphenyl.

In a sixteenth particular embodiment, compounds of Formula I areprovided wherein:

A and D are each independently CH or N;

B is CH;

E is O;

G is N;

Y is —NR₃ or O;

Z is absent or ═O;

n₁ is 1 or 2;

n₂ and n₃ are 1;

n₄ is 0;

R₁ is phenyl, pyridyl or pyrimidinyl, each of which may be optionallysubstituted with one or more substituents (for example, 1-5) selectedfrom R₄;

R₂ is pyrimidinyl, pyridyl, oxadiazolyl, benzoxazole or —C(═O)OR₅,wherein the heteroaryl may be optionally substituted with one or more(for example, 1-5) R₆'s;

R₃ is hydrogen;

R₄, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, phenyl,heteroaryl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH,—SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —C(═O)NR₉S(O)₂R₉,—S(O)₂NR₉C(═O)OR₉, —C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)NR₉R₉,—S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈ and —NR₉S(O₂)R₈, wherein the alkyl,phenyl and heteroaryl may each be optionally substituted with one ormore (for example, 1-5) R₆'s;

R_(4b), at each occurrence, is hydrogen;

R₅ is C1-6 alkyl, C3-6 cycloalkyl or phenyl, each of which may beoptionally substituted with one or more (for example, 1-5) R₆'s;

R₆, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, phenyl,heteroaryl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH,—SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —C(═O)NR₉S(O)₂R₉,—S(O)₂NR₉C(═O)OR₉, —C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)NR₉R₉,—S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈ and —NR₉S(O₂)R₈;

R₈, at each occurrence, is independently C1-6 alkyl or phenyl;

R₉, at each occurrence, is independently hydrogen, C1-6 alkyl, C3-6cycloalkyl or phenyl, wherein the phenyl may optionally be substitutedwith 0-5 R_(9a);

R_(9a), at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄ and —OH;

R₁₀, at each occurrence, is independently C1-6 alkyl, C3-6 cycloalkyl orphenyl, wherein the phenyl may optionally be substituted with 0-5R_(10a);

R_(10a), at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃,—OR₁₄ and —OH; and

R₁₄, at each occurrence, is independently hydrogen or C1-6 alkyl.

In a seventeenth particular embodiment, compounds of Formula I areprovided wherein n₄=0 to give a compound of Formula Ia:

Further subgroups of Formula Ia comprise a subset of each particularembodiment listed herein (for example, embodiments 1-16 and 18-27, butlimited to where n₄=0).

For the general description of the invention and as well as for each ofthe embodiments 1-27 described herein, more particular values are asfollows:

“C6-10 aryl” has a more particular value of phenyl.

“Heteroaryl” has a more particular value (especially for R₄ and R₆) of asingle ring with 6 atoms of which 1-4 and, even more particularly 1-3,atoms are each independently selected from O, S and N and the remainderare selected to be carbons.

Even more particular values for heteroaryl are oxazole, triazole,imidazole and pyrazole.

“One or more R₆'s” has a more particular value of 1-5 of R₆'s which areindependently selected from the listed definition for R₆ for thatembodiment.

“Heterocyclyl” has a more particular value of 1-4 atoms selected from N,O and S, with the remaining atoms being carbon; and an even moreparticular value as a 4- to 6-membered ring with 1-2 members selectedfrom O, S and N and the remaining atoms being carbon.

“One or more substituents selected from R₄” has a more particular valueof 1-5 of R₄.

In an eighteenth particular embodiment, compounds of the presentinvention are selected from the compounds exemplified in the examples.

In a nineteenth particular embodiment, the present invention relates topharmaceutical compositions comprised of a therapeutically effectiveamount of a compound of the present invention (more particularly, acompound according to any of the embodiments described herein), aloneor, optionally, in combination with a pharmaceutically acceptablecarrier and/or one or more other agent(s), for example, a glucagon-likepeptide-1 receptor agonist or fragment thereof.

In a twentieth embodiment, the present invention relates to methods ofmodulating the activity of the GPR119 G protein-coupled receptorcomprising administering to a mammalian patient, for example, a humanpatient, in need thereof a therapeutically effective amount of acompound of the present invention, alone, or optionally, in combinationwith another compound of the present invention and/or at least one othertype of therapeutic agent.

In a twenty-first embodiment, the present invention relates to a methodfor preventing, modulating, or treating the progression or onset ofdiseases or disorders associated with the activity of the GPR119 Gprotein-coupled receptor comprising administering to a mammalianpatient, for example, a human patient, in need of prevention,modulation, or treatment a therapeutically effective amount of acompound of the present invention, alone, or, optionally, in combinationwith another compound of the present invention and/or at least one othertype of therapeutic agent.

Examples of diseases or disorders associated with the activity of theGPR119 G protein-coupled receptor that can be prevented, modulated, ortreated according to the present invention include, but are not limitedto, diabetes, hyperglycemia, impaired glucose tolerance, insulinresistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy,delayed wound healing, atherosclerosis and its sequelae, abnormal heartfunction, myocardial ischemia, stroke, Metabolic Syndrome, hypertension,obesity, dislipidemia, dylsipidemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL,non-cardiac ischemia, infection, cancer, vascular restenosis,pancreatitis, neurodegenerative disease, lipid disorders, cognitiveimpairment and dementia, bone disease, HIV protease associatedlipodystrophy and glaucoma.

In a twenty-second particular embodiment, the present invention relatesto a method for preventing, modulating, or treating the progression oronset of diabetes, hyperglycemia, obesity, dyslipidemia, hypertensionand cognitive impairment comprising administering to a mammalianpatient, for example, a human patient, in need of prevention,modulation, or treatment a therapeutically effective amount of acompound of the present invention, alone, or, optionally, in combinationwith another compound of the present invention and/or at least one othertype of therapeutic agent.

In a twenty-third particular embodiment, the present invention relatesto a method for preventing, modulating, or treating the progression oronset of diabetes, comprising administering to a mammalian patient, forexample, a human patient, in need of prevention, modulation, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In a twenty-fourth particular embodiment, the present invention relatesto a method for preventing, modulating, or treating the progression oronset of hyperglycemia comprising administering to a mammalian patient,for example, a human patient, in need of prevention, modulation, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In a twenty-fifth embodiment, the present invention relates to a methodfor preventing, modulating, or treating the progression or onset ofobesity comprising administering to a mammalian patient, for example, ahuman patient, in need of prevention, modulation, or treatment atherapeutically effective amount of a compound of the present invention,alone, or, optionally, in combination with another compound of thepresent invention and/or at least one other type of therapeutic agent.

In a twenty-sixth particular embodiment, the present invention relatesto a method for preventing, modulating, or treating the progression oronset of dyslipidemia comprising administering to a mammalian patient,for example, a human patient, in need of prevention, modulation, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In a twenty-seventh particular embodiment, the present invention relatesto a method for preventing, modulating, or treating the progression oronset of hypertension comprising administering to a mammalian patient,for example, a human patient, in need of prevention, modulation, ortreatment a therapeutically effective amount of a compound of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of alternative aspects of the inventionnoted herein. It is understood that any and all embodiments of thepresent invention may be taken in conjunction with any other embodimentto describe additional embodiments of the present invention.Furthermore, any elements of an embodiment may be combined with any andall other elements from any of the embodiments to describe additionalembodiments.

DEFINITIONS

This Definition section is listed for convenience, but is subject to thespecific and narrower definitions given for the embodiments and Exampleslisted elsewhere in the specification and the Examples.

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

One enantiomer of a compound of Formula I may display superior activitycompared with the other. Thus, all of the stereochemistries areconsidered to be a part of the present invention. When required,separation of the racemic material can be achieved by high performanceliquid chromatography (HPLC) using a chiral column or by a resolutionusing a resolving agent such as camphonic chloride as described inYoung, S. D. et al., Antimicrobial Agents and Chemotherapy, 2602-2605(1995).

To the extent that compounds of Formula I, and salts thereof, may existin their tautomeric form, all such tautomeric forms are contemplatedherein as part of the present invention.

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or ring is replaced with a selectionfrom the indicated group, provided that the designated atom's or ringatom's normal valency is not exceeded, and that the substitution resultsin a stable compound. When a substituent is keto (i.e., ═O), then 2hydrogens on the atom are replaced.

When any variable (e.g., R₄) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with (R₄)_(m) and m is0-3, then said group may optionally be substituted with up to three R₄groups and R₄ at each occurrence is selected independently from thedefinition of R₄. Also, combinations of substituents and/or variablesare permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups containing 1 to 20carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons andeven more preferably 1-6 carbons, in the normal chain. “Lower alkyl” isintended to include alkyls having 1-5 carbons, particularly 1-3 carbons.Examples include methyl, ethyl, propyl, isopropyl, butyl, t-butyl,isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethyl-pentyl, nonyl, decyl, undecyl, dodecyl, the variousbranched chain isomers thereof, and the like. Alkyl groups mayoptionally include 1 to 4 substituents such as halo, for example F, Br,Cl, or I, or CF₃, alkyl, alkoxy, aryl, aryloxy, aryl(aryl) or diaryl,arylalkyl, arylalkyloxy, alkenyl, cycloalkyl, cycloalkylalkyl,cycloalkylalkyloxy, amino, hydroxy, hydroxyalkyl, acyl, heteroaryl,heteroaryloxy, heteroarylalkyl, heteroarylalkoxy, aryloxyalkyl,alkylthio, arylalkylthio, aryloxyaryl, alkylamido, alkanoylamino,arylcarbonylamino, nitro, cyano, thiol, haloalkyl, trihaloalkyl, and/oralkylthio.

Unless otherwise indicated, the term “alkenyl” as used herein by itselfor as part of another group refers to straight or branched chainradicals of 2 to 20 carbons, preferably 2 to 12 carbons, and morepreferably 2 to 8 carbons in the normal chain, which include one to sixdouble bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl,2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl,3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl,4-dodecenyl, 4,8,12-tetradecatrienyl, and the like, and which may beoptionally substituted with 1 to 4 substituents, namely, halogen,haloalkyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl,amino, hydroxy, heteroaryl, cycloheteroalkyl, alkanoylamino, alkylamido,arylcarbonyl-amino, nitro, cyano, thiol, alkylthio, and/or any of thealkyl substituents set out herein.

Unless otherwise indicated, the term “alkynyl” as used herein by itselfor as part of another group refers to straight or branched chainradicals of 2 to 20 carbons, preferably 2 to 12 carbons and morepreferably 2 to 8 carbons in the normal chain, which include one triplebond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl,4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl,4-heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl,and the like, and which may be optionally substituted with 1 to 4substituents, namely, halogen, haloalkyl, alkyl, alkoxy, alkenyl,alkynyl, aryl, arylalkyl, cycloalkyl, amino, heteroaryl,cycloheteroalkyl, hydroxy, alkanoylamino, alkylamido, arylcarbonylamino,nitro, cyano, thiol, and/or alkylthio, and/or any of the alkylsubstituents set out herein.

Unless otherwise indicated, the term “cycloalkyl” as employed hereinalone or as part of another group includes saturated or partiallyunsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groupscontaining 1 to 10 rings, preferably 1 to 3 rings, and, even moreparticularly, 1 ring, including monocyclic alkyl, bicyclic alkyl (orbicycloalkyl) and tricyclic alkyl. Cycloalkyls as defined herein containa total of 3 to 20 carbons forming the ring, preferably 3 to 15 carbons,more preferably 3 to 10 carbons, forming the ring. A cycloalkyl asdefined herein and, even more particularly, 3-6 carbons may be fused to1 or 2 aromatic rings as described for aryl. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl,

any of which groups may be optionally substituted with 1 to 4substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy,arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl,arylcarbonylamino, amino, nitro, cyano, thiol, and/or alkylthio, and/orany of the substituents defined above for alkyl.

Where alkyl groups as defined above have single bonds for attachment toother groups at two different carbon atoms, they are termed “alkylene”groups and may optionally be substituted as defined above for “alkyl”.

Where alkenyl groups as defined above and alkynyl groups as definedabove, respectively, have single bonds for attachment at two differentcarbon atoms, they are termed “alkenylene groups” and “alkynylenegroups”, respectively, and may optionally be substituted as definedabove for “alkenyl” and “alkynyl”.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo (particularly fluoro and chloro); and “haloalkyl” is intended toinclude both branched and straight-chain saturated aliphatic hydrocarbongroups, for example CF₃, having the specified number of carbon atoms,substituted with 1 or more halogen (for example —C_(v)F_(w) where v=1 to3 and w=1 to (2v+1)).

Unless otherwise indicated, the term “aryl” as employed herein alone oras part of another group refers to monocyclic and bicyclic aromaticgroups containing 6 to 10 carbons in the ring portion (such as phenyl ornaphthyl, including 1-naphthyl and 2-naphthyl) and may optionallyinclude 1 to 3 additional rings fused to a carbocyclic ring or aheterocyclic ring (such as aryl, cycloalkyl, heteroaryl, orcycloheteroalkyl rings

for example

and may be optionally substituted through available carbon atoms with 1,2, or 3 substituents, for example, hydrogen, halo, haloalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl,trifluoromethoxy, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl,cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy,aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl,heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro,cyano, amino, substituted amino wherein the amino includes 1 or 2substituents (which are alkyl, aryl, or any of the other aryl compoundsmentioned in the definitions), thiol, alkylthio, arylthio,heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl,arylcarbonyl, alkyl-aminocarbonyl, arylaminocarbonyl, alkoxycarbonyl,aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino,arylcarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonylamino,or arylsulfon-aminocarbonyl, and/or any of the alkyl substituents setout herein. A more particular definition of “aryl” is a monocyclic orbicyclic group containing only carbons in the ring (for example, phenyl)which may be optionally substituted through available carbon atoms with1, 2 or 3 substituents.

Unless otherwise indicated, the term “lower alkoxy”, “alkoxy”, “aryloxy”or “aralkoxy” as employed herein alone or as part of another groupincludes any of the above alkyl, aralkyl, or aryl groups linked to anoxygen atom.

Unless otherwise indicated, the term “amino” as employed herein alone oras part of another group refers to amino that may be substituted withone or two substituents, which may be the same or different, such asalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl,cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, or thioalkyl. These substituents may befurther substituted with a carboxylic acid and/or any of the R¹ groupsor substituents for R¹ as set out above. In addition, the aminosubstituents may be taken together with the nitrogen atom to which theyare attached to form 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl,4-morpholinyl, 4-thiamorpholinyl, 1-piperazinyl, 4-alkyl-1-piperazinyl,4-arylalkyl-1-piperazinyl, 4-diarylalkyl-1-piperazinyl, 1-pyrrolidinyl,1-piperidinyl, or 1-azepinyl, optionally substituted with alkyl, alkoxy,alkylthio, halo, trifluoromethyl, or hydroxy.

Unless otherwise indicated, the term “lower alkylthio”, “alkylthio”,“arylthio” or “aralkylthio” as employed herein alone or as part ofanother group includes any of the above alkyl, aralkyl, or aryl groupslinked to a sulfur atom.

Unless otherwise indicated, the term “lower alkylamino”, “alkylamino”,“arylamino” or “arylalkylamino” as employed herein alone or as part ofanother group includes any of the above alkyl, aryl, or arylalkyl groupslinked to a nitrogen atom.

As used herein, the term “heterocyclyl” or “heterocyclic system” isintended to mean a stable 4- to 14-membered monocyclic, bicyclic ortricyclic heterocyclic ring which is saturated, partially unsaturated orunsaturated (aromatic) also called “heteroaryl”, and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, NH, O and S and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom, which results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. If specificallynoted, a nitrogen in the heterocycle may optionally be quaternized. Itis preferred that when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother. As used herein, the term “aromatic heterocyclic system” or“heteroaryl” is intended to mean a stable 5- to 7-membered monocyclic orbicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring whichconsists of carbon atoms and from 1 to 4 heteroatoms independentlyselected from the group consisting of N, O and S and is aromatic innature.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 1H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. In another aspect of theinvention, the heterocycles include, but are not limited to, pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, piperidonyl,4-piperidonyl, piperonyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

As noted above, one particular type of heterocycle is a group known as“heteroaryls”. One particular example of “heteroaryl” are those having asingle ring of which 1-4 (and, more particularly, 1-3) members are O, Sand N and the remainder are carbons. Specific examples of heteroarylsare 1H-indazole, 2H,6H-1,5,2-dithiazinyl, indolyl, 4aH-carbazole,4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl,benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl,4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyrazolotriazinyl, pyridazinyl, pyridooxazole, pyridoimidazole,pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl,pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,tetrazolyl, and xanthenyl. In another aspect of the invention, examplesof heteroaryls are indolyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinylisothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyrazolotriazinyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl,pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and tetrazolyl.

The term “heterocyclylalkyl” or “heterocyclyl” as used herein alone oras part of another group refers to heterocyclyl groups as defined abovelinked through a C atom or heteroatom to an alkyl chain.

The term “heteroarylalkyl” or “heteroarylalkenyl” as used herein aloneor as part of another group refers to a heteroaryl group as definedabove linked through a C atom or heteroatom to an alkyl chain, alkylene,or alkenylene as defined above.

The term “cyano” as used herein, refers to a —CN group.

The term “nitro” as used herein, refers to an —NO₂ group.

The term “hydroxy” as used herein, refers to an OH group.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,p. 1418 (1985), the disclosure of which is hereby incorporated byreference.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., the compound of formula I) is a prodrug within the scopeand spirit of the invention.

The term “prodrugs” as employed herein includes esters and carbonatesformed by reacting one or more hydroxyls of compounds of formula I withalkyl, alkoxy, or aryl substituted acylating agents employing proceduresknown to those skilled in the art to generate acetates, pivalates,methylcarbonates, benzoates, and the like.

Various forms of prodrugs are well known in the art and are describedin:

-   a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al.,    Ch. 31, (Academic Press, 1996);-   b) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985);-   c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson    and H. Bundgaard, eds., Ch. 5, pp. 113-191 (Harwood Academic    Publishers, 1991); and-   d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and    Joachim M. Mayer, (Wiley-VCH, 2003).

Said references are incorporated herein by reference.

In addition, compounds of Formula I are, subsequent to theirpreparation, preferably isolated and purified to obtain a compositioncontaining an amount by weight equal to or greater than 99% formula Icompound (“substantially pure” compound I), which is then used orformulated as described herein. Such “substantially pure” compounds ofthe formula I are also contemplated herein as part of the presentinvention.

All stereoisomers of the compounds of the instant invention arecontemplated, either in admixture or in pure or substantially pure form.The compounds of the present invention can have asymmetric centers atany of the carbon atoms including any one of the R substituents and/orexhibit polymorphism. Consequently, compounds of formula I can exist inenantiomeric, or diastereomeric forms, or in mixtures thereof. Theprocesses for preparation can utilize racemates, enantiomers, ordiastereomers as starting materials. When diastereomeric or enantiomericproducts are prepared, they can be separated by conventional methods forexample, chromatographic or fractional crystallization.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to modulateGPR119 or effective to treat or prevent various disorders. As used inthis invention, it is believed that a therapeutically effective amountof a compound is in the range of 0.1-100 mg/kg per day.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) modulating the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety by reference.

The novel compounds of Formula I may be prepared using the reactions andtechniques described in this section. The reactions are performed insolvents appropriate to the reagents and materials employed and aresuitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including solvent,reaction atmosphere, reaction temperature, duration of the experimentand workup procedures, are chosen to be the conditions standard for thatreaction, which should be readily recognized by one skilled in the art.One skilled in the art of organic synthesis understands that thefunctionality present on various portions of the edict molecule must becompatible with the reagents and reactions proposed. Not all compoundsof formula I falling into a given class may be compatible with some ofthe reaction conditions required in some of the methods described. Suchrestrictions to the substituents, which are compatible with the reactionconditions, will be readily apparent to one skilled in the art andalternate methods must be used.

The synthesis routes described in the following schemes are forsimplicity shown for compounds of formula I where G is N or CH, n₂ andn₃ are 1, and n₄ is 0, such that the synthesis is described for thosecompounds of formula I containing a piperidine or cyclohexane ring. Itwill be recognized by those skilled in the art that the synthesis routesdescribed in the following schemes can also be readily applied to thosecompounds of formula I where G is N or CH, n₂ and n₃ are independently0-2, and n₄ is 0-3. It will be further recognized that the appropriatestarting materials for those compounds of formula I where G is N or CH,n₂ and n₃ are independently 0-2, and n₄ is 0-3 are either commerciallyavailable or can be readily prepared by standard procedures known tothose skilled in the art.

Scheme 1 provides a general route to prepare compounds of Formula Iwhere A, B and D are CR_(4b), and E is oxygen. Anilines (1) are eithercommercially available or are readily prepared by one skilled in theart. For example, treatment of commercially available aniline (1, R_(4b)is H) with a cyclic ketone (2) under reductive amination conditions,such as in the presence of sodium triacetoxyborohydride, affords thesubstituted aniline (3). Treatment of (3) with a reagent (4), forexample 1,2-dibromoethane or 1-bromo-2-chloroethane (n₁ is 1, X¹ is Br,X² is Br or Cl, respectively), or 1,3-dibromopropane or1-bromo-3-chloropropane (n₁ is 2, X¹ is Br, X² is Br or Cl,respectively), in the presence of a base such as potassium carbonate orcesium carbonate in a suitable solvent, such as DMF, gives the cyclizedproduct (6) where Z is absent. Likewise, treatment of (3) with a reagent(5), for example chloroacetyl chloride (n₁ is 1, X³ and X⁴ are Cl) or3-chloropropionyl chloride (n₁ is 2, X³ and X⁴ are Cl), in the presenceof a base, such as triethylamine, in a suitable solvent, such asmethylene chloride or THF, gives the cyclized product (6) where Z is acarbonyl group. Alternatively, treatment of (3) with a reagent (5) whereX⁴ is OMe, for example methyl bromoacetate (n₁ is 1, X³ is Br) in thepresence of a base such as sodium hydride in an appropriate solvent,such as THF, gives an O-alkylated ester intermediate, which by heatingunder various conditions, with or without an acid catalyst such asp-toluenesulfonic acid, can produce the cyclized product (6) where Z isa carbonyl group. Treatment of (6) with an appropriate reagent R₁—YH(7), where Y=NR₃, O or S, to afford (8) can be accomplished under a widevariety of conditions familiar to those skilled in the art. For example,when Y is NR₃, the reaction can be accomplished underpalladium-catalyzed coupling conditions, using an appropriate palladiumcatalyst, such as Pd(dppf)Cl₂, Pd₂(dba)₃, Pd(PPh₃)₄ or Pd(OAc)₂, etc.,and a suitable ligand such as BINAP, PPh₃, P(tBu)₃, o-(biphenyl)P(tBu)₂,etc., and a base such as but not limited to NaOtBu or Cs₂CO₃ in asuitable solvent such as DMF, toluene, THF or DME, at elevatedtemperatures, to yield (8) (see Yang, B. H. et al., J. Organomet. Chem.,576:125 (1999) and Urgaonkar, S. et al., J. Org. Chem., 68:8416 (2003),and references cited therein). In a preferred procedure, (6) is treatedwith an appropriate aniline (7) using Pd(dppf)Cl₂ as catalyst, BINAP asthe ligand, NaOtBu as the base in toluene at 100° C., with or withoutmicrowave irradiation, to afford compounds (8). When Y is O, thereaction can be accomplished by a variety of palladium-catalyzedcoupling conditions to afford diaryl ethers (8). For example, treatmentof (6) with a phenol (7) in the presence of a palladium catalyst, suchas Pd(OAc)₂, Pd₂(dba)₃, etc., a ligand such as DPPF, BINAP, P(tBu)₃,o-(biphenyl)P(tBu)₂, etc., and a base such as but not limited to K₂CO₃,or K₃PO₄ in a suitable solvent such as DMF, toluene, THF or DME, atelevated temperatures, affords ethers (8) (for a recent review of diarylether synthesis, see Frlan, R. et al., Synthesis, 2271 (2006)). Diarylethers (8) can also be prepared by the Ullmann coupling reaction, whichinvolves treatment of (6) with a phenol (7) or its sodium salt in thepresence of a copper (I) salt, such as Cu₂O, CuI, CuBr, CuPF₆(MeCN),etc., a suitable base, such as Cs₂CO₃ or NaOtBu, with or without anadded ligand, such as 1,10-phenanthroline, Chxn-Py-Al, PPh₃, etc., in asuitable solvent such as pyridine, toluene, DMF, MeCN, etc, at elevatedtemperatures, to afford ethers (8) (see Frlan, R. et al., Synthesis,2271 (2006)). When Y is S, the reaction can also be accomplished bypalladium-catalyzed coupling of (6) with an aryl thiol (7), for exampleby using Pd₂(dba)₃ or Pd(OAc)₂ as catalyst, a ligand such as Xantphos orDPEphos, a base such as Hunig's base or potassium carbonate, in dioxaneor toluene as solvent at elevated temperature, to afford diarylthioethers (8) (see Itoh, T. et al., Org. Lett., 6:4587 (2006) andreferences therein). Alternatively, diaryl thioethers (8) can also beprepared by the Ullman coupling reaction similar to that described fordiaryl ethers. For example, treatment of (6) with a thiophenol (7) inthe presence of a copper (I) salt, such as Cu₂O, CuI, CuBr, CuPF₆(MeCN),etc., a suitable base, such as Cs₂CO₃or NaOtBu, with or without an addedligand, such as 1,10-phenanthroline, Chxn-Py-Al, PPh₃, etc., in asuitable solvent such as pyridine, toluene, DMF, MeCN, etc, at elevatedtemperatures, affords thioethers (8). Thus, Scheme 1 provides a generalroute to prepare compounds of Formula I where A, B and D are CR_(4b),and E is oxygen.

Scheme 2 provides a general route to prepare compounds of Formula Iwhere A is N, B and D are CR_(4b), and E is oxygen. Pyridines (9) areeither commercially available or are readily prepared by one skilled inthe art. For example, the commercially available 3-hydroxypyridine (9,R_(4b) is H) can be selectively nitrated at the 4-position with nitricacid and sulfuric acid, providing 4-nitropyridine (10, R_(4b) is H) (seeUS 2006/0155128A1). Protection of the phenol functionality of (10) by,for example, but not limited to, methyl ether (PG=methyl) or any of avariety of trialkylsilyl groups (PG=R₃Si), gives (11). The methyl ethercan be prepared by treating (10) with methyl iodide in the presence of abase such as sodium hydride or potassium carbonate, in a solvent such asTHF or DMF. The trialkylsilyl protecting group can be introduced bytreating (10) with a suitable trialkylsilyl chloride or triflate in thepresence of a base such as triethylamine, in a solvent such as THF orCH₂Cl₂. It will be recognized by those skilled in the art thatadditional protecting groups can be employed for phenol (10). For anexcellent reference for alcohol and phenol protecting groups, seeGreene, T. et al., Protecting Groups in Organic Synthesis, John Wiley &Sons, Inc., New York, N.Y. (1991) and references therein. Conversion of(11) to (13) can be accomplished in two ways. Displacement of the nitrogroup can be achieved by treatment of (11) with amine (12) in thepresence of a base, such as potassium carbonate, in a solvent such asDMF, at elevated temperature with or without microwave irradiation.Alternatively, the nitro group of (11) can be reduced by a variety ofreducing agents well known to those skilled in the art, such as byZn/NH₄Cl or SnCl₂, to afford a 4-aminopyridine which can then undergoreductive amination with ketone (2) in the presence of a borohydridereducing agent, such as sodium triacetoxyborohydride. Alternatively, theaminopyridine can be treated with ketone (2) in the presence of an acidcatalyst, such a p-toluenesulfonic acid, to form the imine upon removalof water, by such methods as toluene at reflux with a Dean-Stark trap.The resulting imine can then be reduced with an appropriate borohydridereducing agent, such as with sodium borohydride, in a solvent such asmethanol or THF Deprotection of (13) to liberate the phenol affords(14). When PG is methyl the deprotection can be accomplished using borontribromide, TMSI, or other methods known to those skilled in the art, toprovide the phenol (14). It will be recognized by those skilled in theart that when G is nitrogen and when R₂ is an acid labile protectinggroup, such as BOC, deprotection under acidic conditions may also causeloss of the nitrogen protecting group. In such case (G=N, R₂=BOC) thenitrogen can be reprotected using BOC₂O to afford (14). In the case of(13) where PG is trialkylsilyl, the deprotection can be accomplishedusing tetrabutylammonium fluoride (TBAF) in a solvent such as THF (seeGreene, T. et al., Protecting Groups in Organic Synthesis, John Wiley &Sons, Inc., New York, N.Y. (1991) and references therein). Cyclizationof (14) can be accomplished with the reagents (4) and (5) and a suitablebase at elevated temperature, as described in Scheme 1, to affordcompound (15), where Z is absent or is a carbonyl group. Coupling of(15) with reagent (7) as described in Scheme 1 affords compounds (16),which represent Formula I where A is N, B and D are CR_(4b), and E isoxygen.

An alternate approach to these compounds is described in Scheme 3. Thenitropyridine (10) can be O-alkylated with a suitable reagent, such asthe bromoalkylester (17), in the presence of a suitable base, such assodium hydride or potassium carbonate, to afford (18). Nitro groupreduction as before, such as with Zn/NH₄Cl or SnCl₂, provides (19).Treatment of (19) with ketone (2) under various reductive aminationconditions, as described previously, affords an aminoester (20), whichcan be converted to lactam (21) by heating under various conditions,with or without an acid catalyst, such as p-toluenesulfonic acid.Coupling of (21) with reagent (7) as previously described affords (22),where Z is carbonyl. Reduction of the lactam of (22) can be accomplishedwith a variety of reagents, such as with borane, alane or lithiumaluminum hydride, to afford (24), where Z is absent. Alternatively, theorder of these last two steps can be reversed, such that reduction of(22), for example with borane, gives (23) and subsequent coupling with(7) gives (24).

Scheme 4 provides a general route to prepare compounds of Formula Iwhere B is N, A and D are CR_(4b), and E is oxygen. Pyridines (25) areeither commercially available or are readily prepared by one skilled inthe art. For example, 5-bromo-3-nitro-pyridinol (25, R_(4b) is H) isreadily prepared from 3-nitro-4-hydroxypyridine (see U.S. Pat. No.3,826,643). The phenol functionality of (25) can be protected by, forexample, but not limited to, methyl ether (PG is methyl) or any of avariety of trialkylsilyl groups (PG is R₃Si), to afford (26). The methylether can be prepared by treating (25) with methyl iodide in thepresence of a base such as sodium hydride or potassium carbonate, in asolvent such as THF or DMF. The trialkylsilyl protecting group can beintroduced by treating (25) with a suitable trialkylsilyl chloride ortriflate in the presence of a base such as triethylamine, in a solventsuch as THF or CH₂Cl₂. It will be recognized by those skilled in the artthat additional protecting groups can be employed for phenol (25). Foran excellent reference for alcohol and phenol protecting groups, seeGreene, T. et al., Protecting Groups in Organic Synthesis, John Wiley &Sons, Inc., New York, N.Y. (1991) and references therein. The nitrogroup of (26) can be reduced by a variety of reducing agents well knownto those skilled in the art, such as by Zn/NH₄Cl or SnCl₂, to afford a3-aminopyridine which can then undergo reductive amination with ketone(2) in the presence of a borohydride reducing agent, such as sodiumtriacetoxyborohydride to afford (27). Alternatively, the aminopyridinecan be treated with ketone (2) in the presence of an acid catalyst, sucha p-toluenesulfonic acid, to form the imine upon removal of water, bysuch method as toluene at reflux with a Dean-Stark trap. The resultingimine can then be reduced with an appropriate borohydride reducingagent, such as with sodium borohydride, in a solvent such as methanol orTHF to afford (27). Deprotection of (27) to liberate the phenol affords(28). When PG is methyl the deprotection can be accomplished using borontribromide, TMSI, or other methods known to those skilled in the art, toprovide the phenol (28). It will be recognized by those skilled in theart that when G is nitrogen and when R₂ is an acid labile protectinggroup, such as BOC, deprotection under acidic conditions may also causeloss of the nitrogen protecting group. In such case (G is N, R₂ is BOC)the nitrogen can be reprotected using BOC₂O to afford (28). In the caseof (27) where PG is trialkylsilyl, the deprotection can be accomplishedusing tetrabutylammonium fluoride (TBAF) in a solvent such as THF (seeGreene, T. et al., Protecting Groups in Organic Synthesis, John Wiley &Sons, Inc., New York, N.Y. (1991) and references therein). Cyclizationof (28) can be accomplished with the reagents (4) or (5) and a suitablebase at elevated temperature, as described in Scheme 1, to affordcompound (29), where Z is absent or is a carbonyl group. Coupling of(29) with reagent (7) under a variety of conditions, as described inScheme 1, affords compounds (30), which represent Formula I where B isN, A and D are CR_(4b), and E is oxygen.

Scheme 5 provides a general route to prepare compounds of Formula Iwhere A and D are N, B is CR_(4b), and E is oxygen. Pyrimidines (31) areeither commercially available or are readily prepared by one skilled inthe art. For example, treatment of commercially available4,6-dichloro-5-methoxypyrimidine (31, R_(4b) is H) with 1 equivalent ofamine (12) in the presence of a base such as potassium carbonate orcesium carbonate, in a solvent such as DMF, THF or methylene chloridegives (32). Demethylation can be accomplished with BBr₃ or TMSI, asdescribed in Scheme 2, to afford the hydroxypyrimidine (33). It will berecognized by those skilled in the art that when G is nitrogen and whenR₂ is an acid labile protecting group, such as tert-butyloxycarbonyl(BOC), deprotection under acidic conditions may also cause loss of thenitrogen protecting group. In such case (G is N, R₂ is BOC) the nitrogencan be reprotected using di-tert-butyldicarbonate (BOC₂O) to afford(33). Treatment of (33) with a reagent (4), for example1,2-dibromoethane or 1-bromo-2-chloroethane (n₁ is 1, X¹ is Br, X² is Bror Cl, respectively), or 1,3-dibromopropane or 1-bromo-3-chloropropane(n₁ is 2, X¹ is Br, X² is Br or Cl, respectively), in the presence of abase such as potassium carbonate or cesium carbonate in a suitablesolvent, such as DMF, gives the cyclized product (34) where Z is absent.In a preferred procedure where n₁ is 1 in Formula I, (33) is treatedwith 1-bromo-2-chloroethane and potassium carbonate in DMF at roomtemperature for several hours to afford an N-chloroethyl intermediate.The temperature of the reaction mixture is then raised to 80-100° C. toafford the cyclized product (34) where Z is absent. Alternatively,treatment of (33) with a reagent (5) where X⁴ is OMe, for example methylbromoacetate (n₁ is 1, X³ is Br) in the presence of a base such assodium hydride or cesium carbonate gives an O-alkylated esterintermediate, which by heating under various conditions can produce thecyclized product (34) where Z is a carbonyl group. In a preferredprocedure where n₁ is 1 in Formula I, (33) is treated with methylbromoacetate and cesium carbonate in DMF at room temperature for severalhours to afford an N-alkylated ester intermediate. The temperature ofthe reaction mixture is then raised to 60-80° C. to afford the cyclizedproduct (34) where Z is a carbonyl group. Coupling of (34) with reagent(7) under various conditions as described in Scheme 1 affords (35),which represents Formula I where A and D are N, B is CR_(4b), and E isoxygen.

Compounds of Formula I where E is N can be prepared as described inScheme 6. Dihalo nitro compounds (36) are either commercially availableor are readily prepared by methods known to those skilled in the art.For example, 4,6-dichloro-5-nitropyrimidine (36, X is Cl, A and D are N,B is CH) is commercially available, while 2,4-dichloro-3-nitropyridine(36, X is Cl, A is N, B and D are CH) is readily available from2,4-dihydroxypyridine (see Norman, M. H. et al., J. Med. Chem., 43:4288(2000)). Treatment of (36) with amine (12) in the presence of a basesuch as potassium carbonate or cesium carbonate, in a solvent such asDMF, THF or methylene chloride affords (37). Nitro group reduction canbe accomplished with a variety of reagents, such as with Zn/NH₄Cl orSnCl₂, as previously described, to provide diamine (38). Cyclizationwith reagents (4) or (5) gives compound (39), which can be coupled withreagent (7) as previously described in Scheme 1 to afford (40).

An alternative preparation of these compounds where Y is O or S is shownin Scheme 7. Coupling of (41) with reagent (7) where Y is O or S canprecede bicyclic ring formation, giving (42). This reaction can bereadily accomplished by treatment of (41) with (7), where Y is O or S,in the presence of a base such as potassium carbonate, cesium carbonateor NaH, in a suitable solvent such as DMF, THF or methylene chloride, atroom temperature or elevated temperature, with or without microwaveirradiation, to afford (42). Nitro group reduction can then beaccomplished as previously described in Scheme 6, using Zn/NH₄Cl, SnCl₂,catalytic hydrogenation, or other suitable reagent known to thoseskilled in the art, to afford the diamine (43). As described previously,bicyclic ring formation can be accomplished with reagents (4) or (5) toafford compounds (40), where Z is absent or is a carbonyl, and Y isoxygen or sulfur.

Scheme 8 provides a general route to prepare compounds of Formula Iwhere E is CH₂ and n₁ is 1. Compounds (44) are either commerciallyavailable or readily prepared by methods known to those skilled in theart. For example, 4,6-dichloro-5-formylpyrimidine (44, X is Cl, A and Dare N, B is CH) is commercially available, while2,4-dichloro-3-formylpyridine (44, X is Cl, A is N, B and D are CH) canbe readily prepared from 2-4-dichloropyridine (see Radinov, R. et al.,J. Org. Chem., 56:4793 (1991)). Treatment of (44) with amine (12) in thepresence of a base, such as potassium carbonate, cesium carbonate ortriethylamine, in a solvent such as DMF, THF or methylene chloride,affords (45). Treatment of (45) with an acetylating agent such as aceticanhydride or acetyl chloride in the presence of a base such astriethylamine or pyridine, in a solvent such as THF at elevatedtemperature, with or without microwave irradiation, affords (46) viaN-acetylation followed by intramolecular aldol condensation. Coupling of(46) with reagent (7) under various conditions as described in Scheme 1affords (47). Reduction of the double bond of (47), such as by catalytichydrogenation over Pd/C catalyst, in a solvent such as methanol orethanol, or by other methods known to those skilled in the art, affords(48), which represents compounds of Formula I where E is CH₂, n₁ is 1,and Z is C═O. Further reduction of (48), for example by treating withborane or lithium aluminum hydride in a solvent such as THF or ether, orby other known procedures, affords (49), which represents compounds ofFormula I where E is CH₂, n₁ is 1, and Z is absent.

Scheme 9 provides an alternative route to prepare compounds of Formula Iwhere E is CH₂. Treatment of aldehyde (45) with an appropriateHorner-Emmons reagent (50), such as triethylphosphonoacetate (R is Et),in the presence of a suitable base, such as sodium hydride or potassiumbis(trimethylsilyl)amide (KHMDS), and in a solvent such as THF affordsthe olefin (52) where m is 0. Likewise, (45) can be treated with anappropriate homologated Wittig reagent, such as the phosphorane (51),which can be generated in situ from the correspondingtriphenylphosphonium salt and a base such as potassium t-butoxide, in asolvent such as THF or toluene, and affords the olefin (52) where mis 1. Coupling of (52) with reagent (7) under a variety of conditions asdescribed in Scheme 1 gives (53). Reduction of the olefin, such as bycatalytic hydrogenation over Pd/C catalyst, in a solvent such asmethanol or ethanol, or by other methods known to those skilled in theart, affords a saturated ester. Heating this ester in a solvent such astoluene, with or without an appropriate acid catalyst such asp-toluenesulfonic acid, results in ring closure to produce compound(54), which represents Formula I where E is CH₂ and Z is carbonyl.Further reduction with a reducing such as, but not limited to, borane,lithium aluminum hydride, or alane, in a solvent such as THF or ether,affords compound (54), which represents Formula I where E is CH₂ and Zis absent.

The nature of the R₂ group in Formula I can be varied readily by avariety of procedures known to those skilled in the art, for example asshown in Scheme 10 when G is nitrogen. When G is nitrogen, R₂ in theprevious schemes can represent a nitrogen protecting group, such as butnot limited to a tert-butyloxycarbonyl (BOC) or carbobenzyloxy (CBZ)carbamate. Deprotection of (55) when R₂ is BOC can be accomplished usingHCl or TFA to give (56). When R₂ is CBZ, deprotection can beaccomplished by catalytic hydrogenation to afford (56). It will berecognized to one skilled in the art that R₂ can take the form of avariety of protecting groups (see Greene, T. et al., Protecting Groupsin Organic Synthesis, John Wiley & Sons, Inc., New York, N.Y. (1991) andreferences therein). Treatment of (56) with a variety of alkyl or arylchloroformates, in the presence of a base such as triethylamine, in asolvent such as THF or methylene chloride, affords carbamates (57).Alternatively, treatment of (56) with acid chlorides in the presence ofa base such as triethylamine, in a solvent such as THF or methylenechloride, or with carboxylic acids in the presence of a suitable peptidecoupling agent, such as but not limited to 1-hydroxybenzotriazole (HOBT)or benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate(pyBOP), in a solvent such as THF or methylene chloride, affords theamides (58). One skilled in the art of organic synthesis will recognizethat a wide variety of procedures are known for carrying out thetransformation of (56) to (57) and (58).

Additional methods for varying the substituent R₂ are described inScheme 11, where G is nitrogen. Treatment of (56) with an optionallysubstituted aryl halide or aryl triflate (59) in the presence of asuitable palladium catalyst, ligand and base (see Yang, B. H. et al., J.Organomet. Chem., 576:125 (1999)) affords the aryl substituted compounds(60). Treatment of amine (56) with a cyclic ketone (61) in the presenceof a reducing agent, such as sodium triacetoxyborohydride, affordscycloalkyl substituted analogs (63). Alternatively, treatment of (56)with a cyclic bromide or mesylate (62) in the presence of a base such aspotassium carbonate, cesium carbonate or triethylamine in a solvent suchas THF, DMF or methylene chloride provides the analogs (63). Amine (56)can also be treated with a variety of 5- and 6-membered heterocyclicanalogs (64) or (65) in the presence of a suitable base or under avariety of palladium-catalyzed coupling conditions (see Yang, B. H. etal., J. Organomet. Chem., 576:125 (1999)) to afford the heteroarylsubstituted analogs (66). For example, treatment of (56) with2-chloropyrimidine (64, V and Z are N) and potassium carbonate atelevated temperature in DMF gave the pyrimidine substituted analog (66,heteroaryl is 2-pyrimidinyl).

Utilities and Combinations A. Utilities

The compounds of the present invention possess activity as agonists ofthe GPR119 receptor, and, therefore, may be used in the treatment ofdiseases associated with GPR119 receptor activity. Via the activation ofGPR119 receptor, the compounds of the present invention may preferablybe employed to increase insulin production or increase GLP-1 secretionor both.

Accordingly, the compounds of the present invention can be administeredto mammals, preferably humans, for the treatment of a variety ofconditions and disorders, including, but not limited to, treating,preventing, or slowing the progression of diabetes and relatedconditions, microvascular complications associated with diabetes,macrovascular complications associated with diabetes, cardiovasculardiseases, Metabolic Syndrome and its component conditions, inflammatorydiseases and other maladies. Consequently, it is believed that thecompounds of the present invention may be used in preventing,inhibiting, or treating diabetes, hyperglycemia, impaired glucosetolerance, insulin resistance, hyperinsulinemia, retinopathy,neuropathy, nephropathy, wound healing, atherosclerosis and its sequelae(acute coronary syndrome, myocardial infarction, angina pectoris,peripheral vascular disease, intermittent claudication, myocardialischemia, stroke, heart failure), Metabolic Syndrome, hypertension,obesity, dyslipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, high LDL, vascular restenosis, peripheralarterial disease, lipid disorders, bone disease (includingosteoporosis), PCOS, HIV protease associated lipodystrophy, glaucoma andinflammatory diseases, such as, psoriasis, rheumatoid arthritis andosteoarthritis, and treatment of side-effects related to diabetes,lipodistrophy and osteoporosis from corticosteroid treatment.

Metabolic Syndrome or “Syndrome X” is described in Ford et al., J. Am.Med. Assoc., 287:356-359 (2002) and Arbeeny et al., Curr. Med.Chem.—Imm., Endoc. & Metab. Agents, 1:1-24 (2001).

B. Combinations

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of formula I, alone orin combination with a pharmaceutical carrier or diluent. Optionally,compounds of the present invention can be used alone, in combinationwith other compounds of the invention, or in combination with one ormore other therapeutic agent(s), e.g., an antidiabetic agent or otherpharmaceutically active material.

The compounds of the present invention may be employed in combinationwith other GPR119 receptor agonists or one or more other suitabletherapeutic agents useful in the treatment of the aforementioneddisorders including: anti-diabetic agents, anti-hyperglycemic agents,anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathicagents, anti-nephropathic agents, anti-atherosclerotic agents,anti-ischemic agents, anti-hypertensive agents, anti-obesity agents,anti-dyslipidemic agents, anti-dyslipidemic agents, anti-hyperlipidemicagents, anti-hypertriglyceridemic agents, anti-hypercholesterolemicagents, anti-restenotic agents, anti-pancreatic agents, lipid loweringagents, appetite suppressants, treatments for heart failure, treatmentsfor peripheral arterial disease and anti-inflammatory agents.

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include insulin and insulinanalogs (e.g., LysPro insulin, inhaled formulations comprising insulin);glucagon-like peptides; sulfonylureas and analogs (e.g., chlorpropamide,glibenclamide, tolbutamide, tolazamide, acetohexamide, glypizide,glyburide, glimepiride, repaglinide, meglitinide); biguanides (e.g.,metformin, phenformin, buformin); alpha2-antagonists and imidazolines(e.g., midaglizole, isaglidole, deriglidole, idazoxan, efaroxan,fluparoxan); other insulin secretagogues (e.g., linogliride,insulinotropin, exendin-4,N,N-dimethyl-N′-[2-(4-morpholinyl)phenyl]guanidine (E)-2-butenedioatesalt (BTS-675820),(−)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine (A-4166));thiazolidinediones and PPAR-gamma agonists (e.g., ciglitazone,pioglitazone, troglitazone, rosiglitazone); PPAR-alpha agonists e.g.,fenofibrate, gemfibrozil); PPAR alpha/gamma dual agonists (e.g.,muraglitazar, peliglitazar); SGLT2 inhibitors (e.g.,3-(Benzo[b]furan-5-yl)-2′,6′-dihydroxy-4′-methylpropiophenone-2′-O-(6-O-methoxycarbonyl)-β-d-glucopyranoside(T-1095 Tanabe Seiyaku), phlorizin, TS-033 (Taisho), dapagliflozin(BMS), sergliflozin (Kissei), AVE 2268 (Sanofi-Aventis));11-beta-hydroxysteriod dehydrogenase type I inhibitors (e.g., AMG221,INCB13739); dipeptidyl peptidase-IV (DPP4) inhibitors (e.g.,saxagliptin, sitagliptin, vildagliptin, and denagliptin); glucagon-likepeptide-1 (GLP-1) receptor agonists (e.g., Exenatide (Byetta™), NN2211(Liraglutide, Novo Nordisk), AVE0010 (Sanofi-Aventis), R1583(Roche/Ipsen), SUN E7001 (Daiichi/Santory), GSK-716155 (GSK/Human GenomeSciences) and Exendin-4 (PC-DACTM); aldose reductase inhibitors (e.g.,those disclosed in WO 99/26659); RXR agonists (e.g., reglitizar(JTT-501),5-[[6-[(2-fluorophenyl)methoxy]-2-naphthalenyl]methyl]-2,4-Thiazolidinedione(MCC-555),5-[[3-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-4-(trifluoromethoxy)phenyl]methylene]-2,4-Thiazolidinedione(MX-6054), DRF2593, farglitazar,(±)-5-[2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)phenyl]methyl]benzamide(KRP-297),6-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)cyclopropyl]-3-Pyridinecarboxylicacid (LG100268)); fatty acid oxidation inhibitors (e.g., clomoxir,etomoxir; α-glucosidase inhibitors: precose, acarbose, miglitol,emiglitate, voglibose,2,6-dideoxy-2,6-imino-7-O-β-D-glucopyranosyl-D-glycero-L-gulo-heptitol(MDL-25,637), camiglibose); beta-agonists (e.g., Methylester[4-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]-Aceticacid (BRL 35135),2-[4-[(2S)-2-[[(2S)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]-Aceticacid (BRL 37344),4-[(3R)-3-[bis[(2R)-2-hydroxy-2-phenylethyl]amino]butyl]-Benzamide (Ro16-8714),2-[4-[2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]ethoxy]phenoxy]-N-(2-methoxyethyl)-Acetamide(ICI D7114),5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-3-Benzodioxole-2,2-dicarboxylicacid, disodium salt (CL 316,243), TAK-667, AZ40140); phosphodiesteraseinhibitors, both cAMP and cGMP type (e.g., sildenafil,9-((1S,2R)-2-fluoro-1-methylpropyl)-2-methoxy-6-(1-piperazinyl)purinehydrochloride (L-686398), L-386,398); amylin agonists (e.g.,pramlintide); lipoxygenase inhibitors (e.g., masoprocal); somatostatinanalogs (e.g., lanreotide, seglitide, octreotide); glucagon antagonists(e.g., BAY 276-9955); insulin signaling agonists, insulin mimetics,PTP1B inhibitors (e.g.,2-[2-(1,1-dimethyl-2-propenyl)-1H-indol-3-yl]-3,6-dihydroxy-5-[7-(3-methyl-2-butenyl)-1H-indol-3-yl]-2,5-Cyclohexadiene-1,4-dione(L-783281), TER17411, TER17529); gluconeogenesis inhibitors (e.g.,GP3034); somatostatin analogs and antagonists; antilipolytic agents(e.g., nicotinic acid, acipimox, N-cyclohexyl-2′-O-methyl-Adenosine (WAG994)); glucose transport stimulating agents (e.g.,4-chloro-α-[(4-methylphenyl)sulfonyl]-benzeneheptanoic acid(BM-130795)); glucose synthase kinase inhibitors (e.g., lithiumchloride, CT98014, CT98023); galanin receptor agonists; Chemokinereceptor antagonist CCR2/5 (e.g., NCB3284, MK-0812, INCB8696, maraviroc(Pfizer) and vicriviroc); thyriod receptor agonists (e.g., KB-2115 (KaroBio)); Glucokinase activators (e.g., RO-27-4375, RO-28-1675 (Roche),6-[[3-[(1S)-2-methoxy-1-methylethoxy]-5-[(1S)-1-methyl-2-phenylethoxy]benzoyl]amino]-3-Pyridinecarboxylicacid (GKA-50 AstraZeneca)); GPR119 agonists (e.g., 1,1-dimethylethylester4-[[3-(4-pyridinyl)-1,2,4-oxadiazol-5-yl]methoxy]-1-Piperidinecarboxylicacid (PSN-632408 OSI Prosidion)); GDIR agonists (e.g., APD668 (Arena));GPR40 modulators (e.g.,(S)-4-(dimethylamino)-3-(4-((4-methyl-2-p-tolylthiazol-5-yl)methoxy)phenyl)-4-oxobutanoicacid,6-chloro-2-(4-chlorobenzylthio)-1-(4-(methoxymethoxy)phenyl)-1H-benzo[d]imidazole).

Examples of suitable lipid lowering agents and anti-atheroscleroticagents for use in combination with the compounds of the presentinvention include one or more MTP/ApoB secretion inhibitors (e.g.,dirlopatide,N-(2,2,2-Trifluoroethyl)-9-[4-[4-[[[4′-(trifluoromethyl)[1,1′-biphenyl]-2-yl]carbonyl-]amino]-1-piperidinyl]butyl]-9H-fluorene-9-carboxamide,methanesulfonate, CP-741952 (Pfizer), SLx-4090 (Surface Logix)); HMG CoAreductase inhibitors (e.g., atorvastatin, rosuvastatin, simvastatin,pravastatin, lovastatin, fluvastatin); squalene synthetase inhibitors,PPAR alpha agonists and fibric acid derivatives (e.g., fenofibrate,gemfibrozil); ACAT inhibitors; lipoxygenase inhibitors; cholesterolabsorption inhibitors (e.g., ezetimibe); thyriod receptor agonists(e.g., as set forth above); Ileal Na+/bile acid cotransporter inhibitors(e.g., compounds as disclosed in Drugs of the Future, 24, 425-430(1999); upregulators of LDL receptor activity (e.g.,(3R)-3-[(13R)-β-hydroxy-10-oxotetradecyl]-5,7-dimethoxy-1(3H)-Isobenzofuranone(Taisho Pharmaceutical Co. Ltd) and(3α,4α,5α)-4-(2-propenyl)-Cholestan-3-ol (Eli Lilly); bile acidsequestrants (e.g., WELCHOL®, COLESTID®, LOCHOLEST® AND QUESTRAN®; andfibric acid derivatives, such as ATROMID®, LOPID® AND TRICOT®)cholesterol ester transfer protein inhibitors (e.g., torcetrapib and(2R)-3-{[3-(4-chloro-3-ethyl-phenoxy)-phenyl]-[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl]amino}-1,1,1-trifluoro-2-propanol);nicotinic acid and derivatives thereof (e.g., niacin, acipimox); PCSK9inhibitors; LXR agonists (e.g., those disclosed in U.S. PatentApplication Publication Nos. 2003/01814206, 2005/0080111, and2005/0245515); lipoxygenase inhibitors (e.g., such as benzimidazolederivatives, as disclosed in WO 97/12615, 15-LO inhibitors, as disclosedin WO 97/12613, isothiazolones, as disclosed in WO 96/38144, and 15-LOinhibitors, as disclosed by Sendobry et al., “Attenuation ofdiet-induced atherosclerosis in rabbits with a highly selective15-lipoxygenase inhibitor lacking significant antioxidant properties”,Brit. J. Pharmacology, 120:1199-1206 (1997), and Cornicelli et al.,“15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target forVascular Disease”, Current Pharmaceutical Design, 5:11-20 (1999)).

Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, atavastatin, and rosuvastatin.

Examples of suitable anti-hypertensive agents for use in combinationwith the compounds of the present invention include beta adrenergicblockers, calcium channel blockers (L-type and T-type; e.g., diltiazem,verapamil, nifedipine, amlodipine and mybefradil), diuretics (e.g.,chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide,bendroflumethiazide, methylchlorothiazide, trichloromethiazide,polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone,furosemide, musolimine, bumetanide, triamtrenene, amiloride,spironolactone), renin inhibitors (e.g., aliskiren), ACE inhibitors(e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril,cilazopril, delapril, pentopril, quinapril, ramipril, lisinopril), AT-1receptor antagonists (e.g., losartan, irbesartan, valsartan), ETreceptor antagonists (e.g., sitaxsentan, atrsentan, and compoundsdisclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), Dual ET/AIIantagonist (e.g., compounds disclosed in WO 00/01389), neutralendopeptidase (NEP) inhibitors, vasopeptidase inhibitors (dual NEP-ACEinhibitors) (e.g., omapatrilat and gemopatrilat), nitrates, centralalpha agonists (e.g., clonidine), alpha1 blockers (e.g., prazosine),arterial vasodilators (e.g., minoxidil), sympatolytics (e.g.,resperine), renin inhibitors (e.g., Aliskiren (Novartis)).

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include a cannabinoid receptor 1antagonist or inverse agonist (e.g., rimonabant,(4S)-3-(4-chlorophenyl)-N-[(4-chlorophenyl)sulfonyl]-4,5-dihydro-N′-methyl-4-phenyl-1H-Pyrazole-1-carboximidamide(SLV 319), CP-945598 (Pfizer), Surinabant (SR-147778, Sanofi-Aventis),N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide(Merck) and those discussed in Hertzog, D. L., Expert Opin. Ther.Patents, 14:1435-1452 (2004)); a beta 3 adrenergic agonist (e.g.,rafabegron (AJ9677, Takeda/Dainippon),N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-Benzenesulfonamide(L750355, Merck), or CP331648 (Pfizer) or other known beta 3 agonists,as disclosed in U.S. Pat. Nos. 5,541,204, 5,770,615, 5,491,134,5,776,983, and 5,488,064, with rafabegron,N-[4-[2-[[(2S)-3-[(6-amino-3-pyridinyl)oxy]-2-hydroxypropyl]amino]ethyl]phenyl]-4-(1-methylethyl)-Benzenesulfonamide,and CP331648 being preferred); a lipase inhibitor (e.g., orlistat orcetilistat, with orlistat being preferred); a serotonin andnorepinephrine reuptake inhibitor (e.g., sibutramine, Abbott andtesofensine, Neurosearch) with sibutramine being preferred; a dopaminereuptake inhibitor (e.g., buproprion, GSK); or 5-HT_(2C) agonist, (e.g.,lorcaserin hydrochloride (Arena), WAY-163909[(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole],with lorcaserin hydrochloride being preferred); 5-HT6 receptorantagonists (SUVEN, BIOVITRUM, EPIX), anti-epileptics topiramate(Johnson & Johnson) and zonisamide, a ciliary neurotrophic factoragonist (eg. axokine (REGENERON); brain-derived neurotrophic factor(BDNF), orexin antagonists, histamine receptor-3(H3) modulators,melanin-concentrating hormone receptor (MCHR) antagonists (e.g.,GSK-856464 (GlaxoSmithKline), T-0910792 (Amgen)); diacylglycerolacyltransferase (DGAT) inhibitors (e.g., BAY-74-4113 (Bayer));acetyl-CoA carboxylase (ACC) inhibitors (e.g.,N-(4-(4-(4-isopropoxyphenoxy)phenyebut-3-yn-2-yl)acetamide (A-80040,Abbott),(R)-anthracen-9-yl(3-(morpholine-4-carbonyl)-1,4′-bipiperidin-1′-yl)methanone(CP-640186, Pfizer)), SCD-1 inhibitors as described by Jiang et al,Diabetes 2004, 53, (abs 653-p); amylin receptor agonists (e.g.,compounds disclosed in WO 2005/025504); thyroid receptor agonists (e.g.,as set forth above); growth hormone secretagogue receptor (GHSR)antagonists (e.g., A-778193 (Abbott), leptin and leptin mimetics (e.g.,OB-3 (Aegis/Albany Medical College), leptin analogs A-100 and A-200(Amgen), CBT-001452 (Cambridge Biotechnology), ML-22952 (Millennium)),PYY receptor agonist (e.g., AC-162352 (Amylin), PYY-3-36 (Emishere),PYY(3-36)NH2 (Unigene)), NPY-Y4 agonists (7™ Pharma WO 2005/089786(A2,A3)-1), NPY-5 antagonists (e.g., NPYSRA-972 (AstraZeneca),GW-594884A (GlaxoSmithKline), J-104870 (Banyu)); MTP/apoB secretioninhibitors (as set forth above), and/or an anorectic agent.

The anorectic agent which may be optionally employed in combination withcompounds of the present invention include dexamphetamine, phentermine,phenylpropanolamine, or mazindol, with dexamphetamine being preferred.

Other compounds that can be used in combination with the compounds ofthe present invention include CCK receptor agonists (e.g., SR-27895B);galanin receptor antagonists; MCR-4 antagonists (e.g.,N-acetyl-L-norleucyl-L-glutaminyl-L-histidyl-D-phenylalanyl-L-arginyl-D-tryptophyl-Glycinamide,(HP-228); urocortin mimetics, CRF antagonists, and CRF binding proteins(e.g., mifepristone (RU-486), urocortin).

Further, the compounds of the present invention may be used incombination with HIV protease inhibitors, including but not limited toREYATAZ® and KALETRA®.

Examples of suitable memory enhancing agents, anti-dementia agents, orcognition promoting agents for use in combination with the compounds ofthe present invention include, but are not limited to ARICEPT®,RAZADYNE®, donepezil, rivastigmine, galantamine, memantine, tacrine,metrifonate, muscarine, xanomelline, deprenyl and physostigmine.

Examples of suitable anti-inflammatory agents for use in combinationwith the compounds of the present invention include, but are not limitedto, NSAIDS, prednisone, acetaminophen, aspirin, codeine, fentanyl,ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin,piroxicam, sufentanyl, sunlindac, interferon alpha, prednisolone,methylprednisolone, dexamethazone, flucatisone, betamethasone,hydrocortisone, beclomethasone, REMICADE®, ORENCIA®, and ENBREL®.

The aforementioned patents and patent applications are incorporatedherein by reference.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physicians' Desk Reference, as in thepatents set out above, or as otherwise determined by one of ordinaryskill in the art.

The compounds of formula I can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such as inthe form of tablets, capsules, granules or powders; sublingually;bucally; parenterally, such as by subcutaneous, intravenous,intramuscular, or intrasternal injection, or infusion techniques (e.g.,as sterile injectable aqueous or non-aqueous solutions or suspensions);nasally, including administration to the nasal membranes, such as byinhalation spray; topically, such as in the form of a cream or ointment;or rectally such as in the form of suppositories; in dosage unitformulations containing non-toxic, pharmaceutically acceptable vehiclesor diluents.

In carrying out the method of the invention for treating diabetes andrelated diseases, a pharmaceutical composition will be employedcontaining the compounds of formula I, with or without otherantidiabetic agent(s) and/or antihyperlipidemic agent(s) and/or othertype therapeutic agents in association with a pharmaceutical vehicle ordiluent. The pharmaceutical composition can be formulated employingconventional solid or liquid vehicles or diluents and pharmaceuticaladditives of a type appropriate to the mode of desired administration,such as pharmaceutically acceptable carriers, excipients, binders, andthe like. The compounds can be administered to a mammalian patient,including humans, monkeys, dogs, etc. by an oral route, for example, inthe form of tablets, capsules, beads, granules or powders. The dose foradults is preferably between 1 and 2,000 mg per day, which can beadministered in a single dose or in the form of individual doses from1-4 times per day.

A typical capsule for oral administration contains compounds ofstructure I (250 mg), lactose (75 mg), and magnesium stearate (15 mg).The mixture is passed through a 60 mesh sieve and packed into a No. 1gelatin capsule.

A typical injectable preparation is produced by aseptically placing 250mg of compounds of structure I into a vial, aseptically freeze-dryingand sealing. For use, the contents of the vial are mixed with 2 mL ofphysiological saline, to produce an injectable preparation.

Assay(s) for GPR119 G Protein-Coupled Receptor Activity

The in vitro modulation of GPR119 can be determined as follows.

HIT-T15 cAMP Assay

A HIT-T15 hamster insulinoma cell line can be purchased from ATCC andgrown in the medium recommended by ATCC (i.e., Growth Medium: F12KMedium (Invitrogen 21127-022; 10% D-horse Serum; and 2.5% FBS).

To conduct the cAMP assay, cells are plated on 96 well plates (e.g., BDFalcon: REF 353948, black side, clear bottom, TC surface) at a densityof about 4.5×10⁴ cells per well in growth medium and incubatedovernight. Following incubation, the growth medium is removed from thewells, followed by a single rinse with the assay buffer from the HitHunter cAMP kit (100 μl/well). Following the rinse, 20 μl of assaybuffer is added to each well followed by addition of 10 μl of a 3×concentration of compound working solution. The solution is then mixedwell. The final concentration range of compound is from about 10⁻⁵M toabout 10⁻¹¹M. The reaction is incubated at 37° C., in a 5% CO₂ for 1hour. Following incubation, the cAMP concentration is determined usingthe Hit Hunter cAMP kit according to the manufacturer's protocol.

Human Tet-Inducible cAMP Assay

Cell lines using the Flp-In-T-REx 293 tetracycline inducible geneexpression system are cultured in culture medium comprising thefollowing components: DMEM#11965, 10% FBS, 2 mM L-glutamine, 200 ug/mlHygromycin B, and 15 ug/ml blasticidin.

For cAMP assays, cells are plated on 96 well plates (e.g., BD Falcon:REF 353948, black side, clear bottom, TC surface) at a density of about4.5×10⁴ cells per well in growth medium containing 1.0 ug/mltetracycline (1.0 mg/ml stock). The cells are then incubated for 48hours at 37° C.

Following the incubation, the growth medium is removed from the wellsand the wells rinsed (once) with the assay buffer included in the HitHunter cAMP kit (100 μl/well). Following the wash, 20 μl of assay bufferis added to each well, followed by addition of 10 μl of a 3×concentration compound working solution. The solution is then mixed. Thefinal concentration range of compound is from about 10⁻⁵M to about10⁻¹¹M. The reagents are then incubated at 37° C. at 5% CO₂ for 1 hour.

The manufacturer's protocol may be followed for cAMP determination. TheHit Hunter cAMP kit protocol is outlined for the HIT-T15 cAMP assaysdescribed above.

Luciferase Assay

HEK 293 cells may be plated on poly-D-lysine treated 96-well BD blackside/clear bottom plates at a density of about 3×10⁴ cells/well ingrowth medium. The growth medium may comprise the following: D-MEM (Cat#12430) with high glucose and 10% fetal bovine serum.

Cells may be transfected with vectors comprising native or non-nativeGPR119 sequences using commercially available vectors (e.g., Stratagene)and transfection reagents. The standard manufacturer's protocols may befollowed to transfect the cells. Following transfection, thetransfection medium may be removed and assay medium added to the wellsof the assay plates.

Once the assay plates are prepared, compound dilution plates may bemade. To do so, make a first compound dilution plate using 10 mM of thecompound of interest diluted to about 1 mM in DMSO. Then make 12 pointhalf-log dilutions of the compounds (in DMSO) using an automated liquidhandler. Next, make a second dilution plate by diluting the wells in thefirst plate ten fold (10×) using assay medium. Once the plates arecomplete, the highest dose is about 10 μM and the lowest dose is about0.03 nM.

Once the dilution plates are complete, one can add about 10 μl of the10× compound dilution to the assay plate containing the assay mediumtransiently transfected cells. Tap the plate to mix the reagents andincubate the plate overnight at 37° C., 95% O₂, and 5% CO₂ in anincubator.

Following incubation, a luciferase assay system may be used (e.g.,Stead-Glo Luciferase Assay System from Promega) according to themanufacturer's instructions. Following completion of the reaction,immediately measure the readout of the assay using a top countluminometer.

In general, preferred compounds of the present invention, such asparticular compounds disclosed in the following examples, have beenidentified to modulate the functional activity of GPR119 Gprotein-coupled receptor at concentrations equivalent to, or morepotently than, 10 μM, preferably 5 μM, more preferably 1 μM, and stillmore preferably 0.1 μM, thereby demonstrating compounds of the presentinvention as especially effective modulators of GPR119 G protein-coupledreceptor. Potencies can be calculated and expressed as EC₅₀ values, andrefer to activity measured employing the assay system described above.

ABBREVIATIONS

The following abbreviations are employed in the Examples and elsewhereherein:

EtOAc=ethyl acetateDMF=dimethylformamideTHF=tetrahydrofuranK₂CO₃=potassium carbonateNa₂CO₃=sodium carbonateMgSO₄=magnesium sulfate

SiO₂=Silicon Dioxide

CH₂Cl₂=methylene chlorideMeOH=methanolHCl=hydrochloric acidCs₂CO₃=cesium carbonateKOH=potassium hydroxideDME=1,2-dimethoxyethanePd(dppf)Cl₂=[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)t-BuONa=sodium tert-butoxidePd₂(dba)₃=tris(dibenzylideneacetone)dipalladium (0)BINAP=rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthylmin=minute(s)h or hr=hour(s)mL or ml=milliliterg=gram(s)mg=milligram(s)mmol=millimole(s)μM=micromolarnM=nanomolarLRMS=low resolution mass spectrometryNMR=nuclear magnetic resonance

EXAMPLES

The following working Examples serve to better illustrate, but notlimit, some of the preferred embodiments of the present invention.Unless otherwise indicated, they have been prepared, isolated andcharacterized using the methods disclosed herein. The abbreviations andterms used herein are defined above. Chemical symbols have their usualand customary meanings.

Example 1 tert-Butyl4-(8-(4-(methylsulfonyl)phenylamino)-2H-benzo[b][1,4]oxazin-4(3H)-yl)piperidine-1-carboxylate

Example 1A tert-Butyl4-(3-bromo-2-hydroxyphenylamino)piperidine-1-carboxylate

To a solution of 2-amino-6-bromophenol (4.18 g, 22.35 mmol) andt-butyl-4-oxo-1-piperidinecarboxylate (4.45 g, 22.35 mmol) in 120 mL ofmethylene chloride was added sodium triacetoxyborohydride (5.19 g, 24.59mmol) portionwise. Upon completion of addition, the reaction mixture wasallowed to stir at ambient temperature for 60 min. After this time, thereaction mixture was filtered through a pad of CELITE® 545 filter aidand concentrated to yield a crude product. The crude product waspurified by flash chromatography on silica gel (elution with 0-50%EtOAc/hexane) to afford 5.60 g (68%) of Example 1A as a solid. ¹H NMR(500 MHz, CDCl₃) δ 1.40 (m, 2H), 1.47 (s, 9H), 2.05 (m, 2H), 2.93 (m,2H), 3.42 (m, 1H), 4.11 (m, 2H), 6.60 (d, J=8.3 Hz, 1H), 6.70 (dd,J=7.7, 8.3 Hz, 1H), 6.81 (d, J=7.7 Hz, 1H). LRMS (ESI): 315.2/317.2[M+H]⁺.

Example 1B tert-Butyl4-(8-bromo-2H-benzo[b][1,4]oxazin-4(3H)-yl)piperidine-1-carboxylate

To Example 1A (0.89 g, 2.4 mmol) and K₂CO₃ (4.6 g, 7.2 mmol) in DMF (25mL) was added 1,2-dibromoethane (0.31 mL, 3.4 mmol). Upon completion ofaddition, the reaction mixture was allowed to stir at ambienttemperature for 5 h and then at 80° C. for 2 h. At the conclusion ofthis period, the reaction mixture was diluted with ethyl acetate, washedwith water and brine, dried over MgSO₄ and concentrated. The resultingresidue was purified by flash chromatography on silica gel (elution with0-25% EtOAc/hexane) to afford 0.67 g (70%) of Example 1B as a solid.LRMS (ESI): 355.0 [M+H]⁺.

Example 1

A mixture of Example 1B (41 mg, 0.10 mmol), 4-aminophenylmethyl sulfone(51 mg, 0.10 mmol), Pd(dppf)Cl₂ (8 mg, 0.009 mmol) and t-BuONa (32 mg,0.33 mmol) in toluene (2 mL) was degassed and irradiated in a sealedtube in a microwave reactor at 100° C. for 10 h. At the conclusion ofthis period, the reaction mixture was purified by flash chromatographyon silica gel (elution with 0-50% EtOAc/hexane) to afford 8 mg (13%) ofExample 1 as a solid. ¹H NMR (400 MHz, CDCl₃): δ 1.46 (s, 9H) 1.58-1.66(m, 2H) 1.78 (d, J=12.10 Hz, 2H) 2.79 (s, 2H) 3.01 (s, 3H) 3.24-3.29 (m,2H) 3.71-3.79 (m, 1H) 4.22-4.31 (m, 4H) 6.31 (s, 1H) 6.50 (d, J=8.25 Hz,1H) 6.72-6.78 (m, 1H) 6.80 (t, J=7.97 Hz, 1H) 7.10 (d, J=8.80 Hz, 2H)7.73 (d, J=8.80 Hz, 2H). LRMS (ESI): 488.0 [M+H]⁺.

Example 2 tert-Butyl4-(8-(4-(methylsulfonyl)phenylamino)-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)piperidine-1-carboxylate

Example 2A tert-Butyl4-(8-bromo-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)piperidine-1-carboxylate

To a mixture of Example 1A (0.65 g, 1.76 mmol) and triethylamine (0.40mL, 2.63 mmol) in methylene chloride (18 mL) was added bromoacetylchloride (0.16 mL, 1.93 mmol). Upon completion of addition, the reactionmixture was allowed to stir at ambient temperature for 2 h. After thistime, the reaction mixture was concentrated, and the resulting residuewas purified by flash chromatography on silica gel (elution with 0-50%EtOAc/hexane) to afford 386 mg (54%) of Example 2A as a solid. LRMS(ESI): 411.0/413.0 [M+H]⁺.

Example 2

A mixture of Example 2A (41 mg, 0.10 mmol), 4-aminophenylmethyl sulfone(17 mg, 0.10 mmol), Pd₂(dba)₃ (1.2 mg, 0.002 mmol), BINAP (4.3 mg, 0.006mmol) and t-BuONa (10 mg, 0.10 mmol) in toluene (2 mL) was degassed andstirred at 110° C. for about 16 h. At the conclusion of this period, thereaction mixture was purified by flash chromatography on silica gel(elution with 0-75% EtOAc/hexane) to afford 48 mg (94%) of Example 2 asa solid. ¹H NMR (400 MHz, CDCl₃): δ 1.59 (s, 9H), 1.66-1.80 (m, 4H),2.56 (m, 2H), 2.81 (m, 2H), 3.05 (s, 3H), 4.37 (m, 4H), 4.56 (s, 2H),6.42 (s, 1H), 6.84 (d, 1H, J=7.5 Hz), 7.00 (dd, 1H, J=7.9, 18.4 Hz),7.15 (m, 4H), 7.80 (m, 2H). LRMS (ESI): 402.0 [M+H−C₅H₈O₂]⁺.

Example 3 tert-Butyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 3A tert-Butyl4-(6-chloro-5-methoxypyrimidin-4-ylamino)piperidine-1-carboxylate

To a mixture of 4,6-dichloro-5-methoxypyrimidine (5.34 g, 30 mmol) and4-amino-1-BOC-piperidine (6.30 g, 31.5 mmol) in THF (150 mL) was addedK₂CO₃ (6.22 g, 45 mmol). Upon completion of addition, the reactionmixture was allowed to stir at ambient temperature for about 16 h. Afterthis time, the reaction mixture was filtered through a pad of SiO₂ geland concentrated to afford 9.83 g (96%) of Example 3A as an off-whitesolid. ¹H NMR (400 MHz, CDCl₃): δ 1.40 (m, 2H), 1.47 (s, 9H), 2.04 (m,2H), 2.92 (broad s, 2H), 3.86 (s, 3H), 4.12 (m, 3H), 5.33 (d, 1H, J=1.7Hz), 8.13 (s, 1H). LRMS (ESI): 343.1 [M+H]⁺.

Example 3B tert-Butyl4-(6-chloro-5-hydroxypyrimidin-4-ylamino)piperidine-1-carboxylate

To a solution of Example 3A (16.40 g, 47.8 mmol) in CH₂Cl₂ (480 mL) wasadded boron tribromide (22.6 mL, 239.2 mmol) dropwise at ambienttemperature. The resulting suspension was refluxed for 2 h. After thistime, the reaction mixture was evaporated in vacuo to remove most of thesolvent. To the resulting residue was slowly added 200 mL of MeOH, andthe resulting mixture was refluxed for 3 h. At the conclusion of thisperiod, the reaction mixture was evaporated thoroughly in vacuo to yielda residue. The residue was dissolved in 200 mL of MeOH and 100 mL ofCH₂Cl₂. The pH of the resulting solution was adjusted to 11-12 by addingtriethylamine Once at the prescribed pH, di-tert-butyl-dicarbonate (9.40g, 43.06 mmol) was added portion-wise. Upon completion of addition, thereaction mixture was allowed to stir at ambient temperature for 30 min.After this time, the reaction mixture was concentrated and separatedbetween CH₂Cl₂ and water. The organic layer was washed, dried over MgSO₄and concentrated in vacuo to yield a residue. The residue was purifiedby flash chromatography on silica gel (elution with 0-10% MeOH/CH₂Cl₂)to afford 11.41 g (67%) of Example 3B as a pale solid. ¹H NMR (400 MHz,CDCl₃): δ 1.24 (m, 2H), 1.27 (s, 9H), 1.82 (m, 2H), 2.75 (broad s, 2H),3.88 (m, 3H), 4.18 (broad s, 1H), 7.71 (s, 1H). LRMS (ESI): 329.1[M+H]⁺.

Example 3C tert-Butyl4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

To a mixture of Example 3B (2.35 g, 7.0 mmol) and K₂CO₃ (2.90 g, 21.0mmol) in DMF (35 mL) was added 1-bromo-2-chloroethane (0.87 mL, 10.5mmol). Upon completion of addition, the reaction mixture was allowed tostir at ambient temperature for about 16 hours and then at 100° C. for 3h. At the conclusion of this period, the reaction mixture was dilutedwith ethyl acetate, washed with water and brine, dried over MgSO₄ andconcentrated. The resulting residue was purified by flash chromatographyon silica gel (elution with 0-50% EtOAc/hexane) to afford 1.78 g (70%)of Example 3C as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 1.48 (s,9H), 1.60-1.72 (m, 4H), 2.88 (broad s, 2H), 3.49 (t, 2H), 4.28 (m, 4H),4.86 (m, 1H), 8.03 (s, 1H). LRMS (ESI): 355.1 [M+H]⁺.

Example 3

A mixture of Example 3C (605 mg, 1.71 mmol),2-fluoro-4-(methylsulfonyl)aniline (323 mg, 1.71 mmol), Pd(dppf)Cl₂ (37mg, 0.051 mmol), BINAP (53 mg, 0.085 mmol) and t-BuONa (164 mg, 1.71mmol) in toluene (20 mL) was degassed and stirred at 100° C. for 3 h.After this time, the reaction mixture was concentrated, and theresulting residue was purified by flash chromatography on silica gel(elution with 0-75% EtOAc/hexane) to afford 711 mg (82%) of Example 3 asa pale solid. ¹H NMR (400 MHz, CDCl₃): δ 1.48 (s, 9H), 1.60-1.72 (m,4H), 2.88 (broad s, 2H), 3.05 (s, 3H), 3.47 (t, 2H, J=4.4 Hz), 4.28 (t,4H, J=4.4 Hz), 4.84 (m, 1H), 7.23 (d, 1H, J=4.4 Hz), 7.65 (dd, 1H,J=2.2, 10.4 Hz), 7.70 (dd, 1H, J=2.2, 8.2 Hz), 8.09 (s, 1H), 8.90 (dd,1H, J=7.9, 8.6 Hz). LRMS (ESI): 508.1 [M+H]⁺.

Example 4 tert-Butyl4-(4-(2-fluoro-4-methylphenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 4 was prepared using a similar method as described above forExample 3, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 2-fluoro-4-methylaniline. ¹H NMR (400 MHz, CDCl₃): δ1.47 (s, 9H), 1.60-1.72 (m, 4H), 2.31 (s, 3H), 2.88 (broad s, 2H), 3.44(dd, 2H, J=4.1, 4.7 Hz), 4.24 (t, 4H, J=4.4 Hz), 4.83 (m, 1H), 6.83-6.94(m, 3H), 8.05 (s, 1H), 8.21 (t, 1H, J=8.2 Hz). LRMS (ESI): 444.1 [M+H]⁺.

Example 5 tert-Butyl4-(4-(2-fluoro-4-methoxyphenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 5 was prepared using a similar method as described above forExample 3, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 2-fluoro-4-methoxylaniline. ¹H NMR (400 MHz, CDCl₃): δ1.42-1.49 (m, 9H) 1.60 (d, J=14.30 Hz, 2H) 1.66-1.72 (m, 2H) 2.86 (s,2H) 3.38-3.44 (m, 2H) 3.77 (s, 3H) 4.14-4.31 (m, 4H) 4.73-4.84 (m, 1H)6.57 (s, 1H) 6.64-6.71 (m, 2H) 8.00 (s, 1H) 8.12 (t, J=9.35 Hz, 1H).LRMS (ESI): 460.1 [M+H]⁺.

Example 6 tert-Butyl4-(4-(4-cyano-2-fluorophenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 6 was prepared using a similar method as described above forExample 3, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 4-amino-3-fluorobenzonitrile. ¹H NMR (400 MHz, CDCl₃):δ 1.47 (s, 9H), 1.60-1.72 (m, 4H), 2.88 (broad s, 2H), 3.47 (dd, 2H,J=8.2, 9.3 Hz), 4.26 (dd, 4H, J=4.4, 4.7 Hz), 4.84 (m, 1H), 7.22 (d, 1H,J=3.3 Hz), 7.35 (dd, 1H, J=1.7, 11.0 Hz), 7.42 (d, 1H, J=8.8 Hz), 8.09(s, 1H), 8.84 (dd, 1H, J=8.0. 8.5 Hz). LRMS (ESI): 455.1 [M+H]⁺.

Example 7 tert-Butyl4-(4-(2-chloro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 7 was prepared using a similar method as described above forExample 3, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 2-chloro-4-(methylsulfonyl)aniline. ¹H NMR (400 MHz,CDCl₃): δ 1.48 (s, 9H), 1.60-1.72 (m, 4H), 2.88 (broad s, 2H), 3.05 (s,3H), 3.48 (t, 2H, J=4.4 Hz), 4.30 (m, 4H), 4.85 (m, 1H), 7.65 (s, 1H),7.80 (dd, 1H, J=2.2, 9.3 Hz), 7.85 (d, 1H, J=2.2 Hz), 8.10 (s, 1H), 8.96(d, 1H, J=9.3 Hz). LRMS (ESI): 524.0 [M+H]⁺.

Example 8 iso-Propyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 8AN-(2-Fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine,HCl salt

A mixture of Example 3 (95 mg, 0.19 mmol) in 4 mL of 4M HCl in1,4-dioxane was stirred at ambient temperature for 3 h. After this time,the reaction mixture was evaporated in vacuo to afford Example 8A, whichwas used without further purification. 408.1 [M+H]⁺.

Example 8

To a mixture of Example 8A (95 mg, 0.19 mmol) and triethylamine (0.65mL, 0.47 mmol) in 3 mL of CH₂Cl₂ was added dropwiseisopropylchloroformate (0.19 mL of 1M in toluene, 0.19 mmol). Uponcompletion of addition, the reaction mixture was stirred at ambienttemperature for 0.5 h. At the conclusion of this period, the reactionmixture was evaporated in vacuo, and the resulting residue was purifiedby flash chromatography on silica gel (elution with 0-100% EtOAc/hexane)to afford 68 mg (70% for 2 steps) of Example 8 as an off-white solid. ¹HNMR (400 MHz, CDCl₃): δ 1.26 (d, 6H, J=6.6 Hz), 1.63-1.76 (m, 4H), 2.91(broad s, 2H), 3.05 (s, 3H), 3.49 (d, 2H, J=3.3 Hz), 4.29 (s, 4H), 4.93(m, 2H), 7.65 (broad s, 1H), 7.66 (d, 1H, J=10.4 Hz), 7.71 (d, 1H, J=8.8Hz), 8.14 (s, 1H), 8.83 (broad s, 1H). LRMS (ESI): 494.1 [M+H]⁺.

Example 9 p-Tolyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 9 was prepared using a similar method as described above forExample 8, with the exception that isopropylchloroformate was replacedwith p-tolychloroformate. ¹H NMR (400 MHz, CDCl₃): δ 1.80 (m, 4H), 2.34(s, 3H), 3.05 (s, 3H), 3.15 (m, 2H), 3.51 (dd, 2H, J=4.4, 4.8 Hz), 4.30(t, 2H, J=4.1 Hz), 4.45 (broad s, 2H), 4.92 (m, 1H), 7.00 (d, 2H, J=8.2Hz), 7.16 (d, 2H, J=8.8 Hz), 7.24 (d, 1H, J=4.4 Hz), 7.65 (d, 1H, J=10.5Hz), 7.71 (m, 1H), 8.11 (s, 1H), 8.91 (t, 1H, J=8.2 Hz). LRMS (ESI):542.1 [M+H]⁺.

Example 10 4-Chlorophenyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 10 was prepared using a similar method as described above forExample 8, with the exception that isopropylchloroformate was replacedwith 4-chlorophenylchloroformate. ¹H NMR (400 MHz, CDCl₃): δ 1.80 (m,4H), 3.05 (s, 3H), 3.18 (m, 2H), 3.51 (m, 2H), 4.30 (t, 2H, J=4.4 Hz),4.32 (m, 2H), 4.93 (m, 1H), 7.07 (m, 2H), 7.24 (d, 1H, J=3.8 Hz), 7.33(dd, 2H, J=3.2, 6.6 Hz), 7.65 (dd, 1H, J=1.6, 10.5 Hz), 7.71 (d, 1H,J=8.8 Hz), 8.11 (s, 1H), 8.91 (t, 1H, J=8.2 Hz). LRMS (ESI): 562.0[M+H]⁺.

Example 11 4-Fluorophenyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 11 was prepared using a similar method as described above forExample 8, with the exception that isopropylchloroformate was replacedwith 4-fluorophenylchloroformate. ¹H NMR (400 MHz, CDCl₃): δ 1.80 (m,4H), 3.05 (s, 3H), 3.17 (m, 2H), 3.51 (t, 2H, J=4.4 Hz), 4.30 (t, 2H,J=4.4 Hz), 4.32 (m, 2H), 4.93 (m, 1H), 7.07 (m, 4H), 7.24 (d, 1H, J=3.8Hz), 7.65 (dd, 1H, J=1.6, 10.5 Hz), 7.71 (dd, 1H, J=1.6, 7.2 Hz), 8.11(s, 1H), 8.91 (dd, 1H, J=7.3, 8.2 Hz). LRMS (ESI): 546.0 [M+H]⁺.

Example 12 4-Methoxyphenyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 12 was prepared using a similar method as described above forExample 8, with the exception that isopropylchloroformate was replacedwith 4-methoxyphenylchloroformate. ¹H NMR (400 MHz, CDCl₃): δ 1.80 (m,4H), 3.05 (s, 3H), 3.15 (m, 2H), 3.51 (t, 2H, J=4.4 Hz), 3.80 (s, 3H),4.30 (dd, 2H, J=3.8, 4.4 Hz), 4.44 (broad s, 2H), 4.92 (m, 1H), 6.89 (m,2H), 7.03 (m, 2H), 7.24 (d, 1H, J=3.8 Hz), 7.65 (dd, 1H, J=2.2, 10.4Hz), 7.71 (dd, 1H, J=1.6, 8.8 Hz), 8.11 (s, 1H), 8.91 (dd, 1H, J=7.7,8.2 Hz). LRMS (ESI): 558.1 [M+H]⁺.

Example 13 2-Chlorophenyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 13 was prepared using a similar method as described above forExample 8, with the exception that isopropylchloroformate was replacedwith 2-chlorophenylchloroformate. ¹H NMR (400 MHz, CDCl₃): δ 1.83 (broads, 4H), 3.05 (s, 3H), 3.08-3.20 (m, 2H), 3.50 (dd, 2H, J=4.4, 4.9 Hz),4.30 (t, 2H, J=4.4 Hz), 4.40-4.60 (m, 2H), 4.96 (m, 1H), 7.20-7.30 (m,4H), 7.43 (m, 1H), 7.65 (dd, 1H, J=1.6, 10.5 Hz), 7.71 (dd, 1H, J=1.6,8.8 Hz), 8.11 (s, 1H), 8.92 (dd, 1H, J=8.0, 8.5 Hz). LRMS (ESI): 562.0[M+H]⁺.

Example 14 Cyclopentyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 14 was prepared using a similar method as described above forExample 8, with the exception that isopropylchloroformate was replacedwith cyclopentylchloroformate. ¹H NMR (400 MHz, CDCl₃): δ 1.56-1.73 (m,10H), 1.85 (m, 2H), 2.90 (m, 2H), 3.05 (s, 3H), 3.46 (t, 2H, J=8.8 Hz),4.27 (m, 4H), 4.85 (m, 1H), 5.12 (m, 1H), 7.23 (d, 1H, J=4.4 Hz), 7.65(dd, 1H, J=2.2, 10.5 Hz), 7.70 (dd, 1H, J=1.7, 8.8 Hz), 8.10 (s, 1H),8.90 (dd, 1H, J=8.0, 8.5 Hz). LRMS (ESI): 520.1 [M+H]⁺.

Example 15 iso-Propyl4-(4-(2-fluoro-4-methoxyphenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 15 was prepared from Example 5 using the methods described inExamples 8A and 8. ¹H NMR (400 MHz, CDCl₃): δ 1.26 (d, 6H, J=6.6 Hz),1.60-1.72 (m, 4H), 2.88 (m, 2H), 3.43 (t, 2H, J=4.4 Hz), 3.78 (s, 3H),4.25 (m, 4H), 4.80-4.94 (m, 2H), 6.59 (s, 1H), 6.70 (m, 2H), 8.01 (s,1H), 8.13 (m, 1H). LRMS (ESI): 446.1 [M+H]⁺.

Example 16 iso-Propyl4-(4-(2-chloro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 16 was prepared from Example 7 using the methods described inExamples 8A and 8. ¹H NMR (400 MHz, CDCl₃): δ 1.27 (m, 6H), 1.60-1.74(m, 4H), 2.91 (d, 2H, J=3.3 Hz), 3.05 (s, 3H), 3.30 (t, 4H, J=4.4 Hz),4.84-4.96 (m, 2H), 7.65 (s, 1H), 7.80 (dd, 1H, J=2.2, 8.8 Hz), 7.94 (d,1H, J=2.2 Hz), 8.10 (s, 1H), 8.96 (d, 1H, J=9.4 Hz). LRMS (ESI): 510.0[M+H]⁺.

Example 178-(1-(Benzo[d]oxazol-2-yl)piperidin-4-yl)-N-(2-fluoro-4-(methylsulfonyl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine

A reaction mixture of Example 8A (30 mg, 0.068 mmol),2-chlorobenzoxazole (13 mg, 0.082 mmol) and K₂CO₃ (19 mg, 0.14 mmol) in1 mL of DMF was heated in a sealed vial in the microwave at 160° C. for60 min. At the conclusion of this period, the reaction mixture wasdiluted with ethyl acetate, washed, dried over MgSO₄ and concentrated toyield a residue. The residue was purified by flash chromatography onsilica gel (elution with 0-100 EtOAc/hexane) to afford 10 mg (28%) ofExample 17 as a pale solid. ¹H NMR (400 MHz, CDCl₃): δ 1.85 (m, 4H),3.05 (s, 3H), 3.24-3.30 (m, 2H), 3.47 (t, 2H, J=4.4 Hz), 4.28 (dd, 2H,J=3.9, 4.9 Hz), 4.49 (m, 2H), 5.00 (m, 1H), 7.05 (m, 1H), 7.18 (dd, 1H,J=6.6, 7.7 Hz), 7.23 (d, 1H, J=3.9 Hz), 7.26 (m, 1H), 7.37 (d, 1H, J=7.2Hz), 7.65 (dd, 1H, J=2.2, 10.5 Hz), 7.71 (dd, 1H, J=1.6, 8.8 Hz), 8.11(s, 1H), 8.91 (dd, 1H, J=8.2, 8.8 Hz). LRMS (ESI): 525.0 [M+H]⁺.

Example 188-(1-(Benzo[d]thiazol-2-yl)piperidin-4-yl)-N-(2-fluoro-4-(methylsulfonyl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine

Example 18 was prepared using a similar method as described above forExample 17, with the exception that 2-chlorobenzoxazole was replacedwith 2-chlorobenzothiazole. LRMS (ESI): 541.1 [M+H]⁺.

Example 19N-(2-Fluoro-4-(methylsulfonyl)phenyl)-8-(1-(pyrimidin-2-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine

Example 19 was prepared using a similar method as described above forExample 17, with the exception that 2-chlorobenzoxazole was replacedwith 2-chloropyrimidine. LRMS (ESI): 485.1 [M+H]⁺.

Example 20 iso-Propyl4-(4-(4-cyano-2-fluorophenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 20A iso-Propyl4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

A mixture of Example 3C (1.90 g, 5.35 mmol) in 50 mL of 4M HCl in1,4-dioxane was stirred at ambient temperature for 1 h. After this time,the reaction mixture was evaporated in vacuo to yield a residue. Theresidue was taken up in 50 mL of methylene chloride and thentriethylamine was added to adjust the pH to a pH of 10-11. Once at theprescribed pH, 5.35 mL of isopropylchloroformate (1M in toluene) wasadded dropwise, and then the reaction was stirred at ambient temperaturefor 0.5 h. At the conclusion of this period, the reaction mixture wasevaporated in vacuo, and the resulting residue was purified by flashchromatography on silica gel (elution with 0-100% EtOAc/hexane) toafford 1.71 g (86%) of Example 20A as a white solid. ¹H NMR (400 MHz,CDCl₃): δ 1.27 (d, 6H, J=6.6 Hz), 1.63 (d, 2H, J=9.4 Hz), 1.72 (d, 2H,J=10.5 Hz), 2.90 (d, 2H, J=6.0 Hz), 3.48 (dd, 2H, J=4.1, 4.7 Hz), 4.28(m, 4H), 4.92 (m, 2H), 8.03 (s, 1H). LRMS (ESI): 255.1 [M+H]⁺.

Example 20

A mixture of Example 20A (62 mg, 0.18 mmol),4-amino-3-fluorobenzonitrile (25 mg, 0.18 mmol), Pd(dppf)Cl₂ (5.3 mg,0.0073 mmol), BINAP (6.7 mg, 0.011 mmol) and t-BuONa (17.5 mg, 0.18mmol) in toluene (1.5 mL) was degassed and heated in a sealed vial inthe microwave at 110° C. for 30 min. After this time, the reactionmixture was purified by flash chromatography on silica gel (elution with0-100% EtOAc/hexane) to afford 47 mg (59%) of Example 20 as an off-whitesolid. ¹H NMR (400 MHz, CDCl₃): δ 1.48 (s, 9H), 1.60-1.72 (m, 4H), 2.88(broad s, 2H), 3.05 (s, 3H), 3.47 (t, 2H, J=4.4 Hz), 4.28 (t, 4H, J=4.4Hz), 4.84 (m, 1H), 7.23 (d, 1H, J=4.4 Hz), 7.65 (dd, 1H, J=2.2, 10.4Hz), 7.70 (dd, 1H, J=2.2, 8.2 Hz), 8.09 (s, 1H), 8.90 (dd, 1H, J=7.9,8.6 Hz). LRMS (ESI): 441.1 [M+H]⁺.

Example 21 iso-Propyl4-(4-(4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 21 was prepared using a similar method as described above forExample 20, with the exception that 4-amino-3-fluorobenzonitrile wasreplaced with 4-(methylsulfonyl)aniline. ¹H NMR (400 MHz, CDCl₃): δ 1.27(m, 6H), 1.60-1.80 (m, 4H), 2.90 (d, 2H, J=59.9 Hz), 3.03 (s, 3H), 3.46(s, 2H), 4.26 (m, 4H), 4.85 (m, 1H), 4.94 (m, 1H), 7.01 (s, 1H), 7.84(m, 4H), 8.09 (d, 1H, J=2.7 Hz). LRMS (ESI): 476.1 [M+H]⁺.

Example 22 iso-Propyl4-(4-(4-cyano-2-chlorophenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 22 was prepared using a similar method as described above forExample 20, with the exception that 4-amino-3-fluorobenzonitrile wasreplaced with 4-amino-3-chlorobenzonitrile. ¹H NMR (400 MHz, CDCl₃): δ1.27 (m, 6H), 1.60-1.73 (m, 4H), 2.91 (broad s, 2H), 3.46 (dd, 2H,J=4.1, 4.7 Hz), 4.26 (m, 4H), 4.85 (m, 1H), 4.93 (m, 1H), 7.80 (s, 1H),7.86 (dd, 1H, J=4.4, 17.6 Hz), 8.09 (s, 1H), 8.49 (s, 1H), 8.65 (d, 1H,J=8.6 Hz). LRMS (ESI): 457.1 [M+H]⁺.

Example 23 iso-Propyl4-(4-(2-methylpyridin-3-ylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 23 was prepared using a similar method as described above forExample 20, with the exception that 4-amino-3-fluorobenzonitrile wasreplaced with 3-amino-2-methylpyridine. ¹H NMR (400 MHz, CDCl₃): δ 1.26(d, 6H, J=6.0 Hz), 1.60-1.73 (m, 4H), 2.55 (s, 3H), 2.90 (broad s, 2H),3.46 (dd, 2H, J=4.1, 4.7 Hz), 4.27 (m, 4H), 4.84 (m, 1H), 4.93 (m, 1H),6.50 (s, 1H), 7.15 (dd, 2H, J=8.8, 16.5 Hz), 8.02 (s, 1H), 8.18 (dd, 2H,J=1.7, 5.0 Hz), 8.47 (dd, 1H, J=1.7, 8.3 Hz). LRMS (ESI): 413.1 [M+H]⁺.

Example 24 iso-Propyl4-(4-(4-(methylsulfonyl)phenoxy)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

A mixture of Example 20A (34 mg, 0.10 mmol), 4-methylsulfonylphenol (19mg, 0.10 mmol) and Cs₂CO₃ (65 mg, 0.20 mmol) in toluene (1 mL) washeated in a sealed vial in the microwave at 150° C. for 7 h. At theconclusion of this period, the reaction mixture was diluted with EtOAc,washed by water and brine, dried over MgSO₄, and then concentrated invacuo to yield a residue. The residue was purified by flashchromatography on silica gel (elution with 0-100% EtOAc/hexane) toafford 19 mg (42%) of Example 24 as a pale solid. ¹H NMR (400 MHz,CDCl₃): δ 1.26 (m, 6H), 1.60-1.76 (m, 4H), 2.90 (broad s, 2H), 3.05 (s,3H), 3.51 (t, 2H, J=4.4 Hz), 4.28 (m, 4H), 4.94 (m, 2H), 7.31 (m, 2H),7.95 (m, 3H). LRMS (ESI): 477.0 [M+H]⁺.

Example 25 iso-Propyl4-(4-(2-methylpyridin-3-yloxy)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

A mixture of Example 20A (52 mg, 0.15 mmol), 3-hydroxyl-2-methylpyridine(25 mg, 0.23 mmol) and KOH powder (17 mg, 0.30 mmol) in DME (1.5 mL) washeated in a sealed vial in the microwave at 150° C. for 1.5 h. Afterthis time, the reaction mixture was purified by flash chromatography(elution with 0-100% EtOAc/hexane) to afford 19 mg (30%) of Example 25as a pale solid. ¹H NMR (400 MHz, CDCl₃): δ 1.26 (m, 6H), 1.60-1.76 (m,4H), 2.47 (s, 3H), 2.90 (broad s, 2H), 3.51 (t, 2H, J=4.4 Hz), 4.30 (m,4H), 4.85-4.95 (m, 2H), 7.18 (dd, 1H, J=4.4, 7.7 Hz), 7.40 (d, 1H, J=8.2Hz), 7.90 (s, 1H), 8.38 (s, 1H). LRMS (ESI): 414.1 [M+H]⁺.

Example 26 tert-Butyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 26A tert-Butyl4-(4-chloro-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

To a mixture of Example 3B (1.48 g, 4.50 mmol) and Cs₂CO₃ (1.76 g, 5.40mmol) in DMF (25 mL) was added methyl bromoacetate (0.50 mL, 5.40 mmol).Upon completion of addition, the reaction mixture was allowed to stir atambient temperature for 3 h and then at 65° C. for about 16 h. At theconclusion of this period, the reaction mixture was diluted with ethylacetate, washed with water and brine, dried over MgSO₄ and thenconcentrated to yield a residue. The residue was purified by flashchromatography on silica gel (elution with 0-100% EtOAc/hexane) toafford 0.44 g (27%) of Example 26A as a pale solid. ¹H NMR (400 MHz,CDCl₃): δ 1.49 (s, 9H), 1.63 (m, 2H), 2.70 (m, 2H), 2.80 (broad s, 2H),4.25 (broad s, 2H), 4.79 (s, 2H), 5.04 (m, 1H), 8.39 (s, 1H). LRMS(ESI): 369.1/313.1 [M+H]⁺.

Example 26

Example 26 was prepared from Example 26A using a similar method asdescribed above for Example 3. ¹H NMR (400 MHz, CDCl₃): δ 1.50 (s, 9H),1.65 (d, 2H, J=11.6 Hz), 2.66-2.90 (m, 4H), 3.05 (s, 3H), 4.29 (m, 1H),4.76 (s, 2H), 5.03 (m, 1H), 7.40 (d, 1H, J=4.3 Hz), 7.70 (dd, 1H, J=2.2,10.4 Hz), 7.75 (dd, 1H, J=1.6, 8.8 Hz), 8.34 (s, 1H), 8.97 (dd, 1H,J=8.3, 8.8 Hz). LRMS (ESI): 522.1 [M+H]⁺.

Example 27 iso-Propyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 27 was prepared from Example 26 using the methods described inExamples 8A and 8. ¹H NMR (400 MHz, CDCl₃): δ 1.27 (m, 6H), 1.69 (d, 2H,J=11.5 Hz), 2.70 (m, 2H), 2.85 (broad s, 2H), 3.07 (s, 3H), 4.33 (broads, 2H), 4.76 (s, 2H), 4.94 (m, 1H), 5.05 (m, 1H), 7.40 (d, 1H, J=3.9Hz), 7.70 (dd, 1H, J=2.2, 10.4 Hz), 7.75 (dd, 1H, J=1.6, 8.8 Hz), 8.34(s, 1H), 8.93 (dd, 1H, J=7.9, 8.6 Hz). LRMS (ESI): 508.0 [M+H]⁺.

Example 28 2-Methoxyphenyl4-(4-(4-cyano-2-fluorophenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 28A3-Fluoro-4-(8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-ylamino)benzonitrile,HCl salt

A mixture of Example 6 (540 mg, 1.19 mmol) in 10 mL of 4M HCl in1,4-dioxane was stirred at ambient temperature for 1 h. After this time,the reaction mixture was evaporated in vacuo to afford Example 28A,which was used without further purification. 355.1 [M+H]⁺.

Example 28

To a mixture of Example 28A (30 mg, 0.077 mmol) and triethylamine (32uL, 0.23 mmol) in 2 mL of CH₂Cl₂ was added 2-methoxyphenylchloroformate(12 uL, 0.077 mmol). Upon completion of addition, the reaction mixturewas stirred at ambient temperature for 10 min. At the conclusion of thisperiod, the reaction mixture was purified by flash chromatography(elution with 0-100% EtOAc/hexane) to afford 23 mg (59%) of Example 28as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 1.80 (broad s, 4H),3.03 (broad s, 1H), 3.18 (broad s, 1H), 3.51 (dd, 2H, J=3.8, 5.0 Hz),3.85 (s, 3H), 4.30 (dd, 2H, J=3.9, 4.4 Hz), 4.40 (m, 2H), 4.95 (m, 1H),6.95 (m, 1H), 7.09 (dd, 2H, J=1.6, 8.2 Hz), 7.20 (m, 3H), 7.35 (dd, 1H,J=1.7, 11.0 Hz), 7.44 (d, 1H, J=8.2 Hz), 8.10 (s, 1H), 8.86 (dd, 1H,J=8.2, 8.6 Hz). LRMS (ESI): 505.1 [M+H]⁺.

Example 29 p-Tolyl4-(4-(4-cyano-2-fluorophenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 29 was prepared using a similar method as described above forExample 28, with the exception that 2-methoxyphenylchloroformate wasreplaced with p-tolylchloroformate. ¹H NMR (400 MHz, CDCl₃): δ 1.78 (m,4H), 2.34 (s, 3H), 3.00 (broad s, 1H), 3.15 (broad s, 1H), 3.51 (d, 2H,J=4.4 Hz), 4.30 (t, 2H, J=4.4 Hz), 4.45 (broad s, 2H), 4.91 (m, 1H),6.99 (d, 2H, J=8.2 Hz), 7.16 (d, 2H, J=8.3 Hz), 7.21 (d, 2H, J=8.4 Hz),7.35 (dd, 1H, J=1.7, 11.0 Hz), 7.44 (d, 1H, J=8.8 Hz), 8.10 (s, 1H),8.86 (dd, 1H, J=8.3, 8.8 Hz). LRMS (ESI): 489.1 [M+H]⁺.

Example 30 Cyclopentyl4-(4-(4-cyano-2-fluorophenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 30 was prepared using a similar method as described above forExample 28, with the exception that 2-methoxyphenylchloroformate wasreplaced with cyclopentylchloroformate. ¹H NMR (400 MHz, CDCl₃): δ1.60-1.80 (m, 10H), 1.90 (m, 2H), 2.90 (m, 2H), 3.46 (m, 2H), 4.27 (m,4H), 4.85 (m, 1H), 5.12 (m, 1H), 7.20 (d, 1H, J=3.8 Hz), 7.35 (dd, 1H,J=1.6, 11.0 Hz), 7.43 (d, 1H, J=8.8 Hz), 8.08 (s, 1H), 8.85 (t, 1H,J=8.2 Hz). LRMS (ESI): 467.1 [M+H]⁺.

Example 31 4-Methoxyphenyl4-(4-(4-cyano-2-fluorophenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 31 was prepared using the same method described above forExample 28, with the exception that 2-methoxyphenylchloroformate wasreplaced with 4-methoxyphenylchloroformate. ¹H NMR (500 MHz, CDCl₃) dppm 1.70-1.83 (m, 4H) 3.00 (s, 1H) 3.14 (s, 1H) 3.46-3.52 (m, 2H)3.76-3.81 (m, 3H) 4.25-4.30 (m, 2H) 4.43 (s, 2H) 4.86-4.95 (m, 1H)6.83-6.91 (m, 2H) 6.99-7.04 (m, 2H) 7.21 (d, J=4.40 Hz, 1H) 7.31-7.37(m, 1H) 7.43 (d, J=8.80 Hz, 1H) 8.09 (s, 1H) 8.85 (t, J=8.52 Hz, 1H).LRMS (ESI): 505.5 [M+H]⁺.

Example 323-Fluoro-4-(8-(1-(pyrimidin-2-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-ylamino)benzonitrile

A reaction mixture of3-fluoro-4-(8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-ylamino)benzonitrile,HCl salt from Example 29A (65 mg, 0.167 mmol), 2-chloropyrimidine (23mg, 0.20 mmol) and K₂CO₃ (35 mg, 0.25 mmol) in 1 mL of DMF was heated ina sealed vial in the microwave at 160° C. for 30 min. The reaction waspurified by flash chromatography on silica gel (elution with 0-100EtOAc/hexane) to afford 26 mg (36%) of Example 32 as a pale solid. ¹HNMR (500 MHz, CDCl₃) δ ppm 1.68 (dd, J=12.65, 4.40 Hz, 2H) 1.80 (d,J=9.90 Hz, 2H) 2.98-3.08 (m, 2H) 3.40-3.48 (m, 2H) 4.20-4.28 (m, 2H)4.88-5.05 (m, 3H) 6.48 (t, J=4.67 Hz, 1H) 7.19 (d, J=3.85 Hz, 1H) 7.34(d, J=11.00 Hz, 1H) 7.42 (d, J=8.80 Hz, 1H) 8.09 (s, 1H) 8.31 (d, J=4.95Hz, 2H) 8.85 (t, J=8.52 Hz, 1H). LRMS (ESI): 433.1 [M+H]⁺.

Example 333-Fluoro-4-(8-(1-(4-methylpyrimidin-2-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-ylamino)benzonitrile

Example 33 was prepared using the same method described above forExample 32, with the exception that 2-chloropyrimidine was replaced with2-chloro-4-methylpyrimidine. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.68 (dd,J=12.10, 4.40 Hz, 2H) 1.79 (d, J=9.35 Hz, 2H) 2.32 (s, 3H) 2.93-3.05 (m,2H) 3.41-3.48 (m, 2H) 4.21-4.28 (m, 2H) 4.97 (dd, J=12.65, 3.30 Hz, 3H)6.37 (d, J=4.95 Hz, 1H) 7.19 (d, J=4.40 Hz, 1H) 7.34 (dd, J=11.00, 2.20Hz, 1H) 7.42 (d, J=8.80 Hz, 1H) 8.10 (s, 1H) 8.16 (d, J=4.95 Hz, 1H)8.85 (t, J=8.25 Hz, 1H). LRMS (ESI): 447.5 [M+H]⁺.

Example 344-(8-(1-(Benzo[d]oxazol-2-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-ylamino)-3-fluorobenzonitrile

Example 34 was prepared using the same method described above forExample 32, with the exception that 2-chloropyrimidine was replaced with2-chlorobenzoxazole. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.77-1.89 (m, 4H)3.21-3.30 (m, 2H) 3.41-3.50 (m, 2H) 4.22-4.30 (m, 2H) 4.47 (d, J=13.20Hz, 2H) 4.91-5.03 (m, 1H) 7.03 (t, J=7.15 Hz, 1H) 7.18-7.21 (m, 1H)7.25-7.28 (m, 1H) 7.31-7.37 (m, 2H) 7.43 (d, J=8.80 Hz, 1H) 8.06-8.12(m, 1H) 8.85 (t, J=8.52 Hz, 1H). LRMS (ESI): 472.5 [M+H]⁺.

Example 35 iso-Propyl4-(4-(2-fluoro-4-(1-methyl-1H-imidazol-2-yl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 35 was prepared using the same method described above forExample 20, with the exception that 4-amino-3-fluorobenzonitrile wasreplaced with 2-fluoro-4-(1-methyl-1H-imidazol-2-yl)aniline. ¹H NMR (500MHz, CDCl₃): δ ppm 1.19-1.30 (m, 6H) 1.58-1.73 (m, 4H) 2.90 (s, 2H)3.40-3.48 (m, 2H) 3.75 (s, 3H) 4.20-4.35 (m, 4H) 4.83 (s, 1H) 4.89-4.96(m, 1H) 6.94 (s, 1H) 7.03 (d, J=3.85 Hz, 1H) 7.09 (s, 1H) 7.35 (d,J=8.80 Hz, 1H) 7.41-7.47 (m, 1H) 8.07 (s, 1H) 8.64 (t, J=8.52 Hz, 1H).LRMS (ESI): 496.2 [M+H]⁺.

Example 36N-(2-Chloro-4-(methylsulfonyl)phenyl)-8-(1-(pyrimidin-2-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine

Example 36 was prepared using the same method described above forExample 32, with the exception that3-fluoro-4-(8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-ylamino)benzonitrile,HCl salt was replaced withN-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine,HCl salt. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.65-1.72 (m, 2H) 1.81 (d,J=9.35 Hz, 2H) 3.01-3.08 (m, 5H) 3.42-3.50 (m, 2H) 4.23-4.32 (m, 2H)4.91-5.01 (m, 3H) 6.48 (t, J=4.67 Hz, 1H) 7.63 (s, 1H) 7.74-7.81 (m, 1H)7.93 (d, J=2.20 Hz, 1H) 8.11 (s, 1H) 8.30 (d, J=4.40 Hz, 2H) 8.96 (d,J=8.80 Hz, 1H). LRMS (ESI): 502.1 [M+H]⁺.

Example 37 iso-Propyl4-(4-(4-cyanophenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 37 was prepared using the same method described above forExample 20, with the exception that 4-amino-3-fluorobenzonitrile wasreplaced with 4-aminobenzonitrile. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.23(d, J=6.05 Hz, 6H) 1.60 (d, J=9.90 Hz, 2H) 1.65-1.72 (m, 2H) 2.87 (s,2H) 3.39-3.47 (m, 2H) 4.15-4.35 (m, 4H) 4.81 (t, J=4.12 Hz, 1H)4.87-4.95 (m, 1H) 6.93 (s, 1H) 7.53 (d, J=8.80 Hz, 2H) 7.74 (d, J=8.80Hz, 2H) 8.03 (s, 1H). LRMS (ESI): 423.2 [M+H]⁺.

Example 38 iso-Propyl4-(4-(2-chloro-4-(methoxycarbonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 38 was prepared using the same method described above forExample 20, with the exception that 4-amino-3-fluorobenzonitrile wasreplaced with methyl 4-amino-3-chlorobenzoate. ¹H NMR (500 MHz, CDCl₃):δ ppm 1.24 (d, J=6.05 Hz, 6H) 1.61 (s, 2H) 1.67-1.78 (m, 2H) 2.90 (s,2H) 3.41-3.49 (m, 2H) 3.88 (s, 3H) 4.19-4.40 (m, 4H) 4.79-4.87 (m, 1H)4.89-4.96 (m, 1H) 7.59 (s, 1H) 7.92 (d, J=8.80 Hz, 1H) 8.04 (s, 1H) 8.08(s, 1H) 8.79 (d, J=8.80 Hz, 1H). LRMS (ESI): 490.2 [M+H]⁺.

Example 39 tert-Butyl4-(4-(2-chloro-4-(dimethylcarbamoyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 39 was prepared using the same method described above forExample 3, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 4-amino-3-chloro-N,N-dimethylbenzamide. ¹H NMR (500MHz, CDCl₃): δ ppm 1.46 (s, 9H) 1.61 (d, J=9.35 Hz, 2H) 1.65-1.74 (m,2H) 2.86 (s, 2H) 3.05 (s, 6H) 3.45 (s, 2H) 4.26 (d, J=3.30 Hz, 4H) 4.81(s, 1H) 7.32 (d, J=8.25 Hz, 1H) 7.42 (s, 1H) 7.49 (s, 1H) 8.06 (s, 1H)8.68 (d, J=8.25 Hz, 1H). LRMS (ESI): 517.3 [M+H]⁺.

Example 40 iso-Propyl4-(4-(2-chloro-4-(dimethylcarbamoyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 40 was prepared from Example 39 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.24 (d, J=6.05 Hz,6H) 1.59-1.66 (m, 2H) 1.67-1.74 (m, 2H) 2.89 (s, 2H) 3.05 (s, 6H)3.39-3.46 (m, 2H) 4.19-4.37 (m, 4H) 4.83 (s, 1H) 4.87-4.96 (m, 1H) 7.32(d, J=10.45 Hz, 1H) 7.43 (s, 1H) 7.49 (s, 1H) 8.06 (s, 1H) 8.69 (d,J=8.80 Hz, 1H). LRMS (ESI): 503.2 [M+H]⁺.

Example 41 iso-Propyl4-(4-(2,6-difluoro-4-methoxyphenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 41 was prepared using the same method described above forExample 20, with the exception that 4-amino-3-fluorobenzonitrile wasreplaced with 2,6-difluoro-4-methoxyaniline. NMR (500 MHz, CDCl₃): δ ppm1.24 (t, J=6.32 Hz, 6H) 1.60 (s, 2H) 1.65-1.74 (m, 2H) 2.88 (s, 2H)3.36-3.44 (m, 2H) 3.76 (s, 3H) 4.17-4.35 (m, 4H) 4.79 (s, 1H) 4.86-4.94(m, 1H) 5.92 (s, 1H) 6.52 (d, J=8.80 Hz, 2H) 7.93 (s, 1H). LRMS (ESI):464.2 [M+H]⁺.

Example 42 iso-Propyl4-(4-(3-fluoro-4-methoxyphenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 42 was prepared using the same method described above forExample 20, with the exception that 4-amino-3-fluorobenzonitrile wasreplaced with 3-fluoro-4-methoxyaniline. ¹H NMR (500 MHz, CDCl₃): δ ppm1.24 (t, J=6.05 Hz, 6H) 1.60 (s, 2H) 1.69 (d, J=10.45 Hz, 2H) 2.88 (s,2H) 3.36-3.44 (m, 2H) 3.84 (s, 3H) 4.17-4.36 (m, 4H) 4.80 (s, 1H)4.87-4.96 (m, 1H) 6.55 (s, 1H) 6.89 (t, J=9.07 Hz, 1H) 7.13 (d, J=8.80Hz, 1H) 7.53 (dd, J=13.20, 2.75 Hz, 1H) 8.00 (s, 1H). LRMS (ESI): 446.2[M+H]⁺.

Example 43 tert-Butyl4-(4-(2,6-dichloro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 43 was prepared using the same method described above forExample 3, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 2,6-dichloro-4-(methylsulfonyl)aniline. ¹H NMR (500MHz, CDCl₃): δ ppm 1.46 (s, 9H) 1.57-1.65 (m, 2H) 1.68-1.75 (m, 2H) 2.85(s, 2H) 3.07 (s, 3H) 3.44-3.53 (m, 2H) 4.17-4.31 (m, 4H) 4.74-4.86 (m,1H) 6.53 (s, 1H) 7.88-7.98 (m, 3H). LRMS (ESI): 558.2 [M+H]⁺.

Example 44 iso-Propyl4-(4-(2,6-dichloro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 44 was prepared from Example 43 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.21-1.29 (m, 6H) 1.64(s, 2H) 1.69-1.78 (m, 2H) 2.89 (s, 2H) 3.08 (s, 3H) 3.42-3.50 (m, 2H)4.23-4.37 (m, 4H) 4.79-4.86 (m, 1H) 4.89-4.96 (m, 1H) 6.55 (s, 1H)7.89-7.96 (m, 3H). LRMS (ESI): 544.2 [M+H]⁺.

Example 45 tert-Butyl4-(4-(2-chloro-4-(methoxycarbonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 45 was prepared using the same method described above forExample 3, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with methyl 4-amino-3-chlorobenzoate. ¹H NMR (500 MHz,CDCl₃): δ ppm 1.42 (s, 9H) 1.53-1.61 (m, 2H) 1.63-1.69 (m, 2H) 2.82 (s,2H) 3.36-3.41 (m, 2H) 3.82 (s, 3H) 4.14-4.26 (m, 4H) 4.70-4.82 (m, 1H)7.53 (s, 1H) 7.85 (dd, J=8.80, 2.20 Hz, 1H) 7.97 (s, 1H) 8.02 (s, 1H)8.75 (d, J=8.80 Hz, 1H). LRMS (ESI): 504.3 [M+H]⁺.

Example 464-(8-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-ylamino)-3-chlorobenzoicacid

To tert-butyl4-(4-(2-chloro-4-(methoxycarbonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate(315 mg, 0.625 mmol) from Example 45 in THF (5 ml) and Water (5 ml) wasadded LiOH (29.9 mg, 1.250 mmol). The reaction was stirred at roomtemperature overnight. The reaction was diluted with 1M aq NaOH, washedwith EtOAc. The aqueous layer was adjusted to pH=5-6 with 1M HCl aqsolution and then extracted with EtOAc, the organic layer was evaporatedand dried in vacuo overnight to yield 302 mg (99%) of crude Example 46as an off-white solid. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.48 (s, 9H) 1.66(dd, J=12.37, 8.52 Hz, 2H) 2.91 (s, 2H) 3.44-3.60 (m, 2H) 4.00-4.16 (m,2H) 4.18-4.42 (m, 4H) 4.71-4.90 (m, 1H) 7.90-8.00 (m, 1H) 8.02-8.23 (m,2H) 8.67-8.87 (m, 1H). LRMS (ESI): 490.3 [M+H]⁺.

Example 47 tert-Butyl4-(4-(4-carbamoyl-2-chlorophenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

To4-(8-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-ylamino)-3-chlorobenzoicacid from Example 46 (34 mg, 0.069 mmol) and TEA (0.029 ml, 0.208 mmol)in DCM (2 ml) was added isopropyl chloroformate (1M in toluene, 0.15 mL,0.15 mmol), the mixture was stirred at r.t. for 15 minutes, 2M NH₃ inmethanol (0.22 ml, 0.44 mmol) was added, the resulting suspension wasstirred at room temperature for 30 minutes, the reaction was evaporatedin vacuo and the residue was purified by flash column (eluted by 0-100%EtOAc/Hexane) to yield 13 mg (38%) of Example 47 as a white solid. ¹HNMR (500 MHz, CDCl₃): δ ppm 1.46 (s, 9H) 1.58-1.66 (m, 2H) 1.66-1.74 (m,2H) 2.86 (s, 2H) 3.41-3.50 (m, 2H) 4.15-4.32 (m, 4H) 4.77-4.89 (m, 1H)7.55 (s, 1H) 7.64 (dd, J=8.80, 2.20 Hz, 1H) 7.91 (d, J=2.20 Hz, 1H) 8.08(s, 1H) 8.78 (d, J=8.80 Hz, 1H). LRMS (ESI): 489.2 [M+H]⁺.

Example 48 tert-Butyl4-(4-(2-chloro-4-(methylcarbamoyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

To4-(8-(1-(tert-butoxycarbonyl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-ylamino)-3-chlorobenzoicacid from Example 46 (33 mg, 0.067 mmol) and TEA (0.028 ml, 0.202 mmol)in DCM (2 ml) was added isopropyl chloroformate (1M in toluene, 0.15 mL,0.15 mmol) the mixture was stirred at rt for 30 minutes, methanamine 40%in water (15.69 mg, 0.202 mmol) was added, the resulting suspension wasstirred at room temperature for 30 minutes, the reaction was loaded ontoa flash column and eluted by 0-100% EtOAc/Hexane to yield 12 mg (35%) ofExample 48 as an off-white solid. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.46(s, 9H) 1.59-1.64 (m, 2H) 1.66-1.73 (m, 2H) 2.81-2.93 (m, 2H) 2.99 (d,J=4.95 Hz, 3H) 3.41-3.48 (m, 2H) 4.18-4.32 (m, 4H) 4.75-4.88 (m, 1H)6.08 (d, J=4.95 Hz, 1H) 7.50 (s, 1H) 7.58 (dd, J=8.80, 2.20 Hz, 1H) 7.86(d, J=2.20 Hz, 1H) 8.07 (s, 1H) 8.74 (d, J=8.80 Hz, 1H). LRMS (ESI):503.3 [M+H]⁺.

Example 49 iso-Propyl4-(4-(4-carbamoyl-2-chlorophenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 49 was prepared from Example 47 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.25 (d, J=6.05 Hz,6H) 1.62 (s, 2H) 1.66-1.76 (m, 2H) 2.90 (t, J=12.10 Hz, 2H) 3.40-3.50(m, 2H) 4.22-4.36 (m, 4H) 4.80-4.87 (m, 1H) 4.89-4.97 (m, 1H) 7.55 (s,1H) 7.61-7.68 (m, 1H) 7.91 (d, J=2.20 Hz, 1H) 8.08 (s, 1H) 8.78 (d,J=8.80 Hz, 1H). LRMS (ESI): 475.3 [M+H]⁺.

Example 50 iso-Propyl4-(4-(2-chloro-4-(methylcarbamoyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 50 was prepared from Example 48 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.19-1.29 (m, 6H)1.57-1.67 (m, 2H) 1.67-1.76 (m, 2H) 2.89 (t, J=11.27 Hz, 2H) 2.99 (d,J=4.95 Hz, 3H) 3.40-3.50 (m, 2H) 4.23-4.36 (m, 4H) 4.80-4.85 (m, 1H)4.88-4.95 (m, 1H) 6.09 (d, J=4.95 Hz, 1H) 7.50 (s, 1H) 7.54-7.62 (m, 1H)7.86 (d, J=2.20 Hz, 1H) 8.07 (s, 1H) 8.74 (d, J=8.80 Hz, 1H). LRMS(ESI): 489.3 [M+H]⁺.

Example 51 tert-Butyl4-(4-(2-chloro-4-(2-morpholinoethylcarbamoyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 51 was prepared using the same method described above forExample 48, with the exception that methanamine was replaced with2-morpholinoethanamine. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.46 (s, 9H)1.64-1.70 (m, 2H) 1.75 (s, 2H) 2.50 (s, 4H) 2.59 (t, J=6.05 Hz, 2H) 2.86(s, 2H) 3.43-3.48 (m, 2H) 3.53 (q, J=5.50 Hz, 2H) 3.69-3.76 (m, 4H)4.18-4.32 (m, 4H) 4.76-4.87 (m, 1H) 6.71 (t, J=4.67 Hz, 1H) 7.59 (dd,J=8.80, 2.20 Hz, 1H) 7.88 (d, J=2.20 Hz, 1H) 8.07 (s, 1H) 8.75 (d,J=8.80 Hz, 1H). LRMS (ESI): 602.4 [M+H]⁺.

Example 52 tert-Butyl4-(4-(2-chloro-4-(3-(pyrrolidin-1-yl)propylcarbamoyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 52 was prepared using the same method described above forExample 48, with the exception that methanamine was replaced with3-(pyrrolidin-1-yl)propan-1-amine. ¹H NMR (500 MHz, CDCl₃): δ ppm1.34-1.43 (m, 9H) 1.54-1.63 (m, 2H) 1.68 (d, J=9.90 Hz, 2H) 1.98-2.10(m, 2H) 2.11-2.19 (m, 2H) 3.05-3.13 (m, 8H) 3.15 (t, J=6.60 Hz, 2H) 3.32(q, J=6.23 Hz, 2H) 3.41-3.49 (m, 2H) 3.62 (q, J=6.05 Hz, 2H) 4.23-4.32(m, 2H) 4.75-4.88 (m, 1H) 7.50 (s, 1H) 7.93 (d, J=8.80 Hz, 1H) 8.02-8.11(m, 1H) 8.31 (t, J=5.77 Hz, 1H) 8.76 (d, J=8.80 Hz, 1H). LRMS (ESI):600.4 [M+H]⁺.

Example 53 tert-Butyl4-(4-(2-chloro-4-(2-(pyrrolidin-1-yl)ethylcarbamoyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 53 was prepared using the same method described above forExample 48, with the exception that methanamine was replaced with2-(pyrrolidin-1-yl)ethanamine. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.45 (s,9H) 1.55-1.63 (m, 2H) 1.65-1.72 (m, 2H) 2.07-2.19 (m, 4H) 3.09 (q,J=7.33 Hz, 8H) 3.35 (s, 2H) 3.41-3.48 (m, 2H) 3.61 (d, J=4.95 Hz, 1H)3.87 (s, 1H) 4.22-4.29 (m, 2H) 4.77-4.91 (m, 1H) 7.51 (s, 1H) 8.00 (d,J=8.25 Hz, 1H) 8.05 (s, 1H) 8.13 (s, 1H) 8.57 (s, 1H) 8.79 (d, J=8.25Hz, 1H). LRMS (ESI): 586.4 [M+H]⁺.

Example 54 iso-Propyl4-(4-(2-chloro-4-(2-morpholinoethylcarbamoyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 54 was prepared from Example 51 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.21-1.31 (m, 6H)1.67-1.74 (m, 2H) 1.79 (s, 2H) 2.51 (s, 4H) 2.60 (t, J=6.05 Hz, 2H) 2.90(s, 2H) 3.41-3.49 (m, 2H) 3.53 (q, J=5.50 Hz, 2H) 3.73 (t, J=4.40 Hz,4H) 4.20-4.39 (m, 4H) 4.79-4.87 (m, 1H) 4.88-4.98 (m, 1H) 6.73 (s, 1H)7.51 (s, 1H) 7.60 (d, J=8.80 Hz, 1H) 7.88 (s, 1H) 8.07 (s, 1H) 8.75 (d,J=8.80 Hz, 1H). LRMS (ESI): 588.3 [M+H]⁺.

Example 55 tert-Butyl4-(4-(3,5-dichloropyridin-4-ylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 55 was prepared using the same method described above forExample 3, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 3,5-dichloropyridin-4-amine. ¹H NMR (500 MHz, CDCl₃):δ ppm 1.46 (s, 9H) 1.56-1.67 (m, 2H) 1.70 (s, 2H) 2.85 (s, 2H) 3.44-3.51(m, 2H) 4.15-4.29 (m, 4H) 4.75-4.88 (m, 1H) 6.53 (s, 1H) 7.95 (s, 1H)8.46 (s, 2H). LRMS (ESI): 481.2 [M+H]⁺.

Example 56 iso-Propyl4-(4-(3,5-dichloropyridin-4-ylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 56 was prepared from Example 55 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.19-1.30 (m, 6H)1.59-1.67 (m, 2H) 1.69-1.75 (m, 2H) 2.89 (t, J=11.55 Hz, 2H) 3.42-3.51(m, 2H) 4.19-4.38 (m, 4H) 4.80-4.87 (m, 1H) 4.89-4.95 (m, 1H) 6.52 (s,1H) 7.96 (s, 1H) 8.46 (s, 2H). LRMS (ESI): 467.2 [M+H]⁺.

Example 57 tert-Butyl4-(4-(4-(methylthio)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 57 was prepared using the same method described above forExample 3, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 4-(methylthio)aniline. ¹H NMR (500 MHz, CDCl₃): δ ppm1.40-1.48 (m, 9H) 1.54-1.62 (m, 2H) 1.65-1.71 (m, 2H) 2.43 (s, 3H) 2.84(s, 2H) 3.35-3.43 (m, 2H) 4.14-4.30 (m, 4H) 4.74-4.82 (m, 1H) 6.63 (s,1H) 7.21-7.26 (m, 2H) 7.51 (d, J=8.80 Hz, 2H) 8.01 (s, 1H). LRMS (ESI):458.3 [M+H]⁺.

Example 58 tert-Butyl4-(4-(2-chloro-4-(methylsulfinyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

To tert-butyl4-(4-(4-(methylthio)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylatefrom Example 57 (112 mg, 0.245 mmol) in THF (2 mL) at room temperature,NCS (39.2 mg, 0.294 mmol) was added, the reaction mixture was stirred atroom temperature for 15 min. The reaction was concentrated in vacuo, andthe residue was purified by silica gel flash column, eluted by 20-100%EtOAc/Hexane to afford 33 mg (26.5%) of Example 58 as an off-whitesolid. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.46 (s, 9H) 1.54-1.65 (m, 2H)1.67-1.74 (m, 2H) 2.71 (s, 3H) 2.86 (d, J=9.35 Hz, 2H) 3.40-3.51 (m, 2H)4.17-4.33 (m, 4H) 4.76-4.87 (m, 1H) 7.45 (dd, J=8.80, 2.20 Hz, 1H) 7.49(s, 1H) 7.72 (d, J=2.20 Hz, 1H) 8.04-8.10 (m, 1H) 8.84 (d, J=8.25 Hz,1H). LRMS (ESI): 508.3 [M+H]⁺.

Example 59 tert-Butyl4-(4-(2-methylpyridin-3-ylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 59 was prepared using the same method described above forExample 3, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 2-methylpyridin-3-amine. ¹H NMR (500 MHz, CDCl₃): δppm 1.45 (s, 9H) 1.58-1.65 (m, 2H) 1.66-1.72 (m, 2H) 2.53 (s, 3H) 2.86(d, J=2.20 Hz, 2H) 3.43 (d, J=3.30 Hz, 2H) 4.14-4.29 (m, 4H) 4.72-4.86(m, 1H) 6.47 (s, 1H) 7.13 (dd, J=7.97, 4.67 Hz, 1H) 8.00 (s, 1H) 8.16(d, J=4.40 Hz, 1H) 8.45 (d, J=8.25 Hz, 1H). LRMS (ESI): 427.2 [M+H]⁺.

Example 60 tert-Butyl4-(4-(4-methylpyridin-3-ylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 60 was prepared using the same method described above forExample 3, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 4-methylpyridin-3-amine. ¹H NMR (500 MHz, CDCl₃): δppm 1.45 (s, 9H) 1.55-1.73 (m, 4H) 2.27 (s, 3H) 2.85 (s, 2H) 3.38-3.48(m, 2H) 4.16-4.30 (m, 4H) 4.73-4.86 (m, 1H) 6.33 (s, 1H) 7.10 (d, J=4.95Hz, 1H) 7.96 (s, 1H) 8.21 (d, J=4.95 Hz, 1H) 9.02 (s, 1H). LRMS (ESI):427.3 [M+H]⁺.

Example 61 (S)-sec-butyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

To (S)-butan-2-ol (9.02 mg, 0.122 mmol) and phosgene (60.2 mg, 0.122mmol) in THF (1.5 mL), TEA (0.034 mL, 0.243 mmol) was added dropwise atroom temperature, the reaction was stirred for 15 minutes, and thenN-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine,HCl from Example 8A (45 mg, 0.101 mmol) was added, the resultingreaction mixture was stirred at room temperature for 15 minutes. Thereaction was diluted by EtOAc, washed by water and brine, dried overMgSO4, evaporated in vacuo. The residue was purified by a silica gelflash column, eluted by 0-50% EtOAc/Hexane to yield 44 mg (82%) ofExample 61 as a pale solid. ¹H NMR (500 MHz, CDCl₃): δ ppm 0.90 (t,J=7.42 Hz, 3H) 1.18-1.24 (m, 3H) 1.51-1.64 (m, 4H) 1.67-1.75 (m, 2H)2.90 (s, 2H) 3.02 (s, 3H) 3.39-3.49 (m, 2H) 4.22-4.35 (m, 4H) 4.68-4.78(m, 1H) 4.84 (s, 1H) 7.20 (d, J=4.40 Hz, 1H) 7.63 (d, J=11.00 Hz, 1H)7.68 (d, J=8.80 Hz, 1H) 8.07 (s, 1H) 8.88 (t, J=8.25 Hz, 1H). LRMS(ESI): 508.2 [M+H]⁺.

Example 62 (R)-sec-butyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 62 was prepared using the same method described above forExample 61, with the exception that (S)-butan-2-ol was replaced with(R)-butan-2-ol. ¹H NMR (500 MHz, CDCl₃): δ ppm 0.90 (t, J=7.42 Hz, 3H)1.17-1.26 (m, 3H) 1.49-1.64 (m, 4H) 1.70 (d, J=13.20 Hz, 2H) 2.86-2.91(m, 2H) 3.02 (s, 3H) 3.40-3.48 (m, 2H) 4.20-4.37 (m, 4H) 4.69-4.77 (m,1H) 4.83 (t, J=4.12 Hz, 1H) 7.20 (d, J=3.85 Hz, 1H) 7.63 (d, J=10.45 Hz,1H) 7.68 (d, J=8.80 Hz, 1H) 8.07 (s, 1H) 8.88 (t, J=8.25 Hz, 1H). LRMS(ESI): 508.2 [M+H]⁺.

Example 63 tert-Butyl4-(4-(2-methylpyridin-3-ylamino)-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 63 was prepared using the same method described above forExample 26, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 2-methylpyridin-3-amine. ¹H NMR (500 MHz, CDCl₃): δppm 1.42-1.53 (m, 9H) 1.59-1.70 (m, 2H) 2.55 (s, 3H) 2.64-2.86 (m, 4H)4.25 (d, J=3.85 Hz, 2H) 4.72 (s, 2H) 4.96-5.04 (m, 1H) 6.69 (s, 1H) 7.19(dd, J=8.25, 4.95 Hz, 1H) 8.20 (s, 1H) 8.27 (d, J=4.40 Hz, 1H) 8.39 (d,J=8.25 Hz, 1H). LRMS (ESI): 441.1 [M+H]⁺.

Example 64 iso-Propyl4-(4-(2-methylpyridin-3-ylamino)-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 64 was prepared from Example 63 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.20-1.32 (m, 6H) 1.65(d, J=11.55 Hz, 2H) 2.56 (s, 3H) 2.65-2.77 (m, 2H) 2.82 (s, 2H) 4.32 (s,2H) 4.72 (s, 2H) 4.88-4.97 (m, 1H) 4.97-5.06 (m, 1H) 6.69 (s, 1H) 7.20(dd, J=7.97, 4.67 Hz, 1H) 8.20 (s, 1H) 8.27 (d, J=3.30 Hz, 1H) 8.41 (d,J=8.25 Hz, 1H). LRMS (ESI): 427.2 [M+H]⁺.

Example 65 tert-Butyl4-(4-(2-methylpyridin-3-yloxy)-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

A reaction mixture of Example 26A (74 mg, 0.2 mmol),3-hydroxyl-2-methylpyrimidine (26 mg, 0.24 mmol) and K₂CO₃ (33 mg, 0.24mmol) in 1.5 mL of DMF was heated in a sealed vial in the microwave at140° C. for 10 min. The reaction was purified by flash chromatography onsilica gel (elution with 0-100 EtOAc/hexane) to afford 25 mg (28%) ofExample 65 as a pale foam. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.42-1.52 (m,9H) 1.65 (d, J=11.55 Hz, 2H) 2.39-2.45 (m, 3H) 2.64-2.88 (m, 4H) 4.22(s, 2H) 4.76 (s, 2H) 4.97-5.05 (m, 1H) 7.20 (s, 1H) 7.40 (d, J=6.60 Hz,1H) 8.12 (s, 1H) 8.42 (d, J=3.30 Hz, 1H). LRMS (ESI): 442.1 [M+H]⁺.

Example 66 tert-Butyl4-(4-(2-chloro-4-(methylsulfonyl)phenylamino)-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 66 was prepared using the same method described above forExample 26, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 2-chloro-4-(methylsulfonyl)aniline. ¹H NMR (500 MHz,CDCl₃): δ ppm 1.38-1.45 (m, 9H) 1.60 (d, J=11.00 Hz, 2H) 2.55-2.69 (m,2H) 2.75 (s, 2H) 2.98-3.06 (m, 3H) 3.22 (s, 2H) 4.17 (s, 2H) 4.68-4.78(m, 2H) 4.90-5.01 (m, 1H) 7.74-7.81 (m, 1H) 7.91 (d, J=2.20 Hz, 1H) 8.26(s, 1H) 8.92 (d, J=8.80 Hz, 1H). LRMS (ESI): 538.1 [M+H]⁺.

Example 67 iso-Propyl4-(4-(2-chloro-4-(methylsulfonyl)phenylamino)-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 67 was prepared from Example 66 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.26 (d, J=5.50 Hz,6H) 1.66 (d, J=11.55 Hz, 2H) 2.64-2.76 (m, 2H) 2.83 (s, 2H) 3.06 (s, 3H)4.34 (s, 2H) 4.77 (s, 2H) 4.89-4.97 (m, 1H) 4.98-5.09 (m, 1H) 7.78-7.89(m, 2H) 7.98 (d, J=2.20 Hz, 1H) 8.33 (s, 1H) 8.99 (d, J=8.80 Hz, 1H).LRMS (ESI): 524.1 [M+H]⁺.

Example 684-(2-Chloro-4-(methylsulfonyl)phenylamino)-8-(1-(pyrimidin-2-yl)piperidin-4-yl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one

Example 68 was prepared using the same method described above forExample 32, with the exception that3-Fluoro-4-(8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-ylamino)benzonitrile,HCl salt was replaced with4-(2-chloro-4-(methylsulfonyl)phenylamino)-8-(piperidin-4-yl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one,HCl salt. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.64-1.75 (m, 2H) 1.81 (d,J=9.35 Hz, 2H) 3.00-3.07 (m, 3H) 3.41-3.50 (m, 2H) 4.24-4.33 (m, 2H)4.89-5.04 (m, 3H) 6.48 (t, J=4.95 Hz, 1H) 7.63 (s, 1H) 7.75-7.82 (m, 1H)7.93 (d, J=2.20 Hz, 1H) 8.11 (s, 1H) 8.30 (d, J=4.40 Hz, 2H) 8.96 (d,J=9.35 Hz, 1H). LRMS (ESI): 516.1 [M+H]⁺.

Example 69 tert-Butyl4-(4-(6-methylpyridin-3-ylamino)-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 69 was prepared using the same method described above forExample 26, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 6-methylpyridin-3-amine. ¹H NMR (500 MHz, CDCl₃): δppm 1.47 (s, 9H) 1.56-1.67 (m, 2H) 2.51 (s, 3H) 2.62-2.71 (m, 2H)2.72-2.90 (m, 2H) 4.28 (s, 2H) 4.68 (s, 2H) 4.91-5.04 (m, 1H) 6.88 (s,1H) 7.14 (d, J=8.25 Hz, 1H) 8.13 (dd, J=8.52, 2.47 Hz, 1H) 8.20 (s, 1H)8.53 (d, J=2.75 Hz, 1H). LRMS (ESI): 441.3 [M+H]⁺.

Example 70 tert-Butyl4-(4-(5-methylpyridin-3-ylamino)-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 70 was prepared using the same method described above forExample 26, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 5-methylpyridin-3-amine. ¹H NMR (500 MHz, CDCl₃): δppm 1.47 (s, 9H) 1.59-1.67 (m, 2H) 2.36 (s, 3H) 2.63-2.73 (m, 2H) 2.82(d, 2H) 4.27 (d, J=17.05 Hz, 2H) 4.69 (s, 2H) 4.94-5.04 (m, 1H) 6.89 (s,1H) 8.10 (s, 1H) 8.15 (s, 1H) 8.24 (s, 1H) 8.49 (d, J=2.75 Hz, 1H). LRMS(ESI): 441.3 [M+H]⁺.

Example 71 tert-Butyl4-(4-(2,6-dimethylpyridin-3-ylamino)-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 71 was prepared using the same method described above forExample 26, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 2,6-dimethylpyridin-3-amine. ¹H NMR (500 MHz, CDCl₃):δ ppm 1.43-1.50 (m, 9H) 1.59-1.67 (m, 2H) 2.50 (s, 6H) 2.62-2.74 (m, 2H)2.75-2.89 (m, 2H) 4.29 (s, 2H) 4.71 (s, 2H) 4.92-5.04 (m, 1H) 6.57 (s,1H) 7.04 (d, J=8.25 Hz, 1H) 8.09 (d, J=7.70 Hz, 1H) 8.16 (s, 1H). LRMS(ESI): 455.3 [M+H]⁺.

Example 72 iso-Propyl4-(4-(6-methylpyridin-3-ylamino)-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 72 was prepared from Example 69 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.24 (t, J=7.15 Hz,6H) 1.66 (s, 2H) 2.72 (d, J=20.89 Hz, 3H) 2.82 (s, 2H) 4.26 (s, 2H)4.61-4.89 (m, 2H) 4.88-5.07 (m, 4H) 7.29-7.57 (m, 2H) 8.23 (s, 2H) 8.78(s, 1H). LRMS (ESI): 427.2 [M+H]⁺.

Example 73 iso-Propyl4-(4-(2,6-dimethylpyridin-3-ylamino)-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 73 was prepared from Example 71 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.20-1.29 (m, 6H) 1.66(d, J=9.90 Hz, 2H) 2.45-2.55 (m, 6H) 2.63-2.77 (m, 2H) 2.83 (s, 2H) 4.27(dd, J=12.10, 4.40 Hz, 2H) 4.71 (s, 2H) 4.87-4.96 (m, 1H) 4.96-5.05 (m,1H) 6.58 (s, 1H) 7.05 (d, J=8.25 Hz, 1H) 8.09 (d, J=8.25 Hz, 1H) 8.17(s, 1H). LRMS (ESI): 441.2 [M+H]⁺.

Example 74 tert-Butyl4-(8-(2-chloro-4-(methylsulfonyl)phenylamino)-2H-benzo[b][1,4]oxazin-4(3H)-yl)piperidine-1-carboxylate

Example 74 was prepared using the same method described above forExample 1, with the exception that 4-aminophenylmethyl sulfone wasreplaced with 2-chloro-4-(methylsulfonyl)aniline. ¹H NMR (500 MHz,CDCl₃): δ ppm 1.45-1.52 (m, 9H) 1.60-1.67 (m, 2H) 1.80 (d, J=12.65 Hz,2H) 2.81 (s, 2H) 2.99-3.07 (m, 3H) 3.25-3.32 (m, 2H) 3.71-3.82 (m, 1H)4.21-4.37 (m, 4H) 6.59 (d, J=8.25 Hz, 1H) 6.66-6.75 (m, 2H) 6.84 (t,J=8.25 Hz, 1H) 7.30 (d, J=8.80 Hz, 1H) 7.59-7.66 (m, 1H) 7.89 (d, J=2.20Hz, 1H). LRMS (ESI): 538.1 [M+H]⁺.

Example 75 iso-Propyl4-(8-(2-chloro-4-(methylsulfonyl)phenylamino)-2H-benzo[b][1,4]oxazin-4(3H)-yl)piperidine-1-carboxylate

Example 75 was prepared from Example 74 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.20-1.28 (m, 6H) 1.61(d, J=8.80 Hz, 2H) 1.79 (d, J=12.10 Hz, 2H) 2.83 (t, J=12.37 Hz, 2H)3.01 (s, 3H) 3.22-3.30 (m, 2H) 3.72-3.81 (m, 1H) 4.19-4.40 (m, 4H)4.85-4.97 (m, 1H) 6.57 (d, J=7.70 Hz, 1H) 6.65-6.72 (m, 2H) 6.82 (t,J=7.97 Hz, 1H) 7.28 (d, J=8.80 Hz, 1H) 7.60 (dd, J=8.80, 2.20 Hz, 1H)7.87 (d, J=2.20 Hz, 1H). LRMS (ESI): 524.1 [M+H]⁺.

Example 76 tert-Butyl4-(8-(2-methylpyridin-3-ylamino)-2H-benzo[b][1,4]oxazin-4(3H)-yl)piperidine-1-carboxylate

Example 76 was prepared using the same method described above forExample 1, with the exception that 4-aminophenylmethyl sulfone wasreplaced with 2-methylpyridin-3-amine. ¹H NMR (500 MHz, CDCl₃): δ ppm1.48 (s, 9H) 1.63-1.70 (m, 2H) 1.80 (d, J=12.10 Hz, 2H) 2.53 (s, 3H)2.80 (s, 2H) 3.25-3.34 (m, 2H) 3.76 (t, J=3.30 Hz, 1H) 4.18-4.34 (m, 4H)5.75 (s, 1H) 6.40 (d, J=8.25 Hz, 1H) 6.48 (d, J=7.70 Hz, 1H) 6.75 (t,J=7.97 Hz, 1H) 7.05 (dd, J=8.25, 4.40 Hz, 1H) 7.58 (d, J=7.15 Hz, 1H)8.10 (d, J=3.30 Hz, 1H). LRMS (ESI): 425.2 [M+H]⁺.

Example 77 iso-Propyl4-(8-(2-methylpyridin-3-ylamino)-2H-benzo[b][1,4]oxazin-4(3H)-yl)piperidine-1-carboxylate

Example 77 was prepared from Example 76 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.25 (d, J=6.60 Hz,6H) 1.58-1.69 (m, 2H) 1.79 (d, J=12.10 Hz, 2H) 2.51 (s, 3H) 2.82 (t,J=12.37 Hz, 2H) 3.22-3.31 (m, 2H) 3.72-3.81 (m, 1H) 4.22-4.39 (m, 4H)4.86-4.97 (m, 1H) 5.74 (s, 1H) 6.39 (d, J=8.25 Hz, 1H) 6.46 (d, J=8.25Hz, 1H) 6.73 (t, J=8.25 Hz, 1H) 7.04 (dd, J=7.97, 4.67 Hz, 1H) 7.56 (d,J=7.15 Hz, 1H) 8.08 (d, J=3.30 Hz, 1H). LRMS (ESI): 411.3 [M+H]⁺.

Example 78N-(2-methylpyridin-3-yl)-4-(1-(pyrimidin-2-yl)piperidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-amine

Example 78 was prepared using the same method described above forExample 32, with the exception that3-Fluoro-4-(8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-ylamino)benzonitrile,HCl salt was replaced withN-(2-methylpyridin-3-yl)-4-(piperidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-amine,HCl salt. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.65-1.75 (m, 2H) 1.91 (d,J=12.10 Hz, 2H) 2.53 (s, 3H) 2.90-3.01 (m, 2H) 3.26-3.34 (m, 2H) 3.93(t, J=3.57 Hz, 1H) 4.24-4.32 (m, 2H) 4.97 (d, J=13.75 Hz, 2H) 5.75 (s,1H) 6.43-6.54 (m, 3H) 6.77 (t, J=7.97 Hz, 1H) 7.05 (dd, J=8.25, 4.95 Hz,1H) 7.59 (d, J=8.25 Hz, 1H) 8.10 (d, J=3.30 Hz, 1H) 8.32 (d, J=4.95 Hz,2H). LRMS (ESI): 403.3 [M+H]⁺.

Example 79 tert-Butyl4-(8-(3,5-dichloropyridin-4-ylamino)-2H-benzo[b][1,4]oxazin-4(3H)-yl)piperidine-1-carboxylate

Example 79 was prepared using the same method described above forExample 1, with the exception that 4-aminophenylmethyl sulfone wasreplaced with 3,5-dichloropyridin-4-amine. ¹H NMR (500 MHz, CDCl₃): δppm 1.46 (s, 9H) 1.55-1.64 (m, 2H) 1.78 (d, J=12.10 Hz, 2H) 2.79 (s, 2H)3.22-3.30 (m, 2H) 3.68-3.80 (m, 1H) 4.17-4.35 (m, 4H) 6.15 (d, J=7.70Hz, 1H) 6.34 (s, 1H) 6.52 (d, J=7.70 Hz, 1H) 6.72 (t, J=7.97 Hz, 1H)8.32 (s, 2H). LRMS (ESI): 479.2 [M+H]⁺.

Example 80 iso-Propyl4-(8-(3,5-dichloropyridin-4-ylamino)-2H-benzo[b][1,4]oxazin-4(3H)-yl)piperidine-1-carboxylate

Example 80 was prepared from Example 79 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.25 (d, J=6.60 Hz,6H) 1.61 (d, J=9.90 Hz, 2H) 1.79 (d, J=12.10 Hz, 2H) 2.75-2.88 (m, 2H)3.20-3.32 (m, 2H) 3.69-3.82 (m, 1H) 4.21-4.39 (m, 4H) 4.86-4.97 (m, 1H)6.15 (d, J=7.70 Hz, 1H) 6.34 (s, 1H) 6.52 (d, J=8.25 Hz, 1H) 6.72 (t,J=7.97 Hz, 1H) 8.32 (s, 2H). LRMS (ESI): 465.2 [M+H]⁺.

Example 81 tert-Butyl4-(8-(2-methylpyridin-3-ylamino)-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)piperidine-1-carboxylate

Example 81 was prepared using the same method described above forExample 2, with the exception that 4-aminophenylmethyl sulfone wasreplaced with 2-methylpyridin-3-amine. ¹H NMR (500 MHz, CDCl₃): δ ppm1.48 (s, 9H) 1.76 (d, J=11.42 Hz, 2H) 2.47-2.54 (m, 3H) 2.53-2.63 (m,2H) 2.78 (d, J=7.91 Hz, 2H) 3.46 (t, J=7.03 Hz, 1H) 4.20-4.42 (m, 2H)4.57 (s, 2H) 5.76 (s, 1H) 6.69 (t, J=9.45 Hz, 2H) 6.89 (t, J=8.35 Hz,1H) 7.10 (dd, J=7.91, 4.83 Hz, 1H) 7.55 (d, J=7.91 Hz, 1H) 8.20 (d,J=4.39 Hz, 1H). LRMS (ESI): 439.3 [M+H]⁺.

Example 82 iso-Propyl4-(8-(2-methylpyridin-3-ylamino)-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)piperidine-1-carboxylate

Example 82 was prepared from Example 81 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.21-1.31 (m, 6H) 1.78(d, J=12.10 Hz, 2H) 2.52 (s, 3H) 2.56 (dd, J=12.65, 4.40 Hz, 2H) 2.82(s, 2H) 4.21-4.44 (m, 3H) 4.57 (s, 2H) 4.86-4.99 (m, 1H) 5.77 (s, 1H)6.69 (dd, J=14.30, 8.25 Hz, 2H) 6.89 (t, J=8.25 Hz, 1H) 7.10 (dd,J=7.97, 4.67 Hz, 1H) 7.55 (d, J=6.60 Hz, 1H) 8.20 (d, J=4.95 Hz, 1H).LRMS (ESI): 425.3 [M+H]⁺.

Example 83 tert-Butyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 83A tert-butyl4-(4-chloro-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

To Example 3B (440 mg, 1.34 mmol) and K2CO3 (555 mg, 4.01 mmol) in DMF(13 ml), 1-bromo-3-chloropropane (421 mg, 2.68 mmol) was added. Thereaction mixture was stirred at room temperature for 60 minutes, andthen at 50° C. overnight, and then at 100° C. till completion. Thereaction was diluted with EtOAc, washed by water and brine, dried overMgSO4, concentrated in vacuo. The residue was purified by Flash ColumnChromatography (eluted with 0-25% EtOAc/Hexane) to afford 208 mg (42%)of Example 83A as a pale solid. ¹H NMR (500 MHz, CDCl₃): δ1.46 (s, 9H)1.58 (d, J=8.25 Hz, 2H) 1.72 (d, J=10.45 Hz, 2H) 2.02-2.11 (m, 2H) 2.82(s, 2H) 3.51-3.59 (m, 2H) 4.20 (t, 2H) 4.31 (t, J=6.60 Hz, 2H) 4.59-4.70(m, 1H) 8.05 (s, 1H). LRMS (ESI): 369.2 [M+H]⁺.

Example 83B iso-propyl4-(4-chloro-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 83B was prepared using the same method described above forExample 20A, with the exception that Example 3C was replaced withExample 83A. ES⁺: found 355.2

Example 83 tert-Butyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 83 was prepared using the same method described above forExample 3, with the exception that Example 3C was replaced with Example83B. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.46 (s, 9H) 1.58 (d, J=7.15 Hz, 2H)1.74 (d, J=10.45 Hz, 2H) 2.03-2.12 (m, 2H) 2.77-2.93 (m, 2H) 3.03 (s,3H) 3.54 (t, J=5.77 Hz, 2H) 4.21 (s, 2H) 4.36 (t, J=6.60 Hz, 2H)4.56-4.68 (m, J=12.03, 12.03, 3.99, 3.85 Hz, 1H) 7.53 (d, J=3.85 Hz, 1H)7.64 (dd, J=10.45, 2.20 Hz, 1H) 7.69 (d, J=8.80 Hz, 1H) 8.08 (s, 1H)8.90 (t, J=8.25 Hz, 1H). LRMS (ESI): 522.2 [M+H]⁺.

Example 84 iso-Propyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 84 was prepared from Example 83 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.24 (t, J=6.32 Hz,6H) 1.59 (d, J=9.90 Hz, 2H) 1.76 (d, J=10.45 Hz, 2H) 2.03-2.10 (m, 2H)2.80-2.94 (m, 2H) 2.99-3.06 (m, 3H) 3.53 (t, J=5.77 Hz, 2H) 4.31 (s, 2H)4.36 (t, J=6.60 Hz, 2H) 4.61-4.69 (m, 1H) 4.86-4.96 (m, 1H) 7.52 (t,J=4.40 Hz, 1H) 7.63 (dd, J=10.45, 2.20 Hz, 1H) 7.68 (d, J=8.80 Hz, 1H)8.08 (s, 1H) 8.90 (t, J=8.52 Hz, 1H). LRMS (ESI): 508.2 [M+H]⁺.

Example 85 tert-Butyl4-(4-(2-methylpyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 85 was prepared using the same method described above forExample 83, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 2-methylpyridin-3-amine. ¹H NMR (500 MHz, CDCl₃): δppm 1.42-1.49 (m, 9H) 1.58 (d, J=9.35 Hz, 2H) 1.75 (d, J=12.10 Hz, 2H)2.01-2.11 (m, 2H) 2.53 (s, 3H) 2.83 (s, 2H) 3.53 (t, J=6.05 Hz, 2H) 4.21(s, 2H) 4.36 (t, J=6.32 Hz, 2H) 4.56-4.65 (m, 1H) 6.82 (s, 1H) 7.15 (dd,J=8.25, 4.95 Hz, 1H) 8.01 (s, 1H) 8.17 (d, J=3.30 Hz, 1H) 8.46 (d,J=8.25 Hz, 1H). LRMS (ESI): 441.2 [M+H]⁺.

Example 86 iso-Propyl4-(4-(2-methylpyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 86 was prepared from Example 85 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.25 (t, J=6.87 Hz,6H) 1.59 (s, 2H) 1.76 (d, J=11.55 Hz, 2H) 2.00-2.10 (m, 2H) 2.53 (s, 3H)2.87 (s, 2H) 3.53 (t, J=6.05 Hz, 2H) 4.27 (d, J=18.15 Hz, 2H) 4.35 (t,J=6.32 Hz, 2H) 4.56-4.67 (m, 1H) 4.84-4.96 (m, 1H) 6.82 (s, 1H) 7.14(dd, J=7.97, 4.67 Hz, 1H) 8.00 (s, 1H) 8.16 (d, J=3.30 Hz, 1H) 8.46 (d,J=8.25 Hz, 1H). LRMS (ESI): 427.3 [M+H]⁺.

Example 87 tert-Butyl4-(4-(2,6-dimethylpyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 87 was prepared using the same method described above forExample 83, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 2,6-dimethylpyridin-3-amine. ¹H NMR (500 MHz, CDCl₃):δ ppm 1.47 (s, 9H) 1.58 (d, J=8.80 Hz, 2H) 1.68 (s, 2H) 1.99-2.14 (m,2H) 2.48 (d, J=6.60 Hz, 6H) 2.84 (s, 2H) 3.53 (t, J=5.77 Hz, 2H) 4.21(t, 2H) 4.35 (t, J=6.32 Hz, 2H) 4.52-4.69 (m, 1H) 6.68 (s, 1H) 7.00 (d,J=8.25 Hz, 1H) 7.98 (s, 1H) 8.17 (d, J=8.25 Hz, 1H). LRMS (ESI): 455.3[M+H]⁺.

Example 88 iso-Propyl4-(4-(2,6-dimethylpyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 88 was prepared from Example 87 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.25 (d, J=6.05 Hz,6H) 1.59 (d, J=8.80 Hz, 2H) 1.76 (d, J=10.45 Hz, 2H) 2.00-2.14 (m, 2H)2.53 (d, J=8.25 Hz, 6H) 2.87 (s, 2H) 3.53 (t, J=5.77 Hz, 2H) 4.15-4.41(m, 4H) 4.56-4.70 (m, 1H) 4.85-4.99 (m, 1H) 6.72 (s, 1H) 7.04 (d, J=8.25Hz, 1H) 7.98 (s, 1H) 8.27 (d, J=7.70 Hz, 1H). LRMS (ESI): 441.3 [M+H]⁺.

Example 89 tert-Butyl4-(4-(3,5-dichloropyridin-4-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 89 was prepared using the same method described above forExample 83, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 3,5-dichloropyridin-4-amine. ¹H NMR (500 MHz, CDCl₃):δ ppm 1.47 (s, 9H) 1.60 (s, 4H) 2.04-2.18 (m, 2H) 2.83 (s, 2H) 3.50-3.64(m, 2H) 4.21 (s, 2H) 4.36 (t, J=6.60 Hz, 2H) 4.55-4.70 (m, 1H) 6.77 (s,1H) 7.96 (s, 1H) 8.48 (s, 2H). LRMS (ESI): 495.2 [M+H]⁺.

Example 90 iso-Propyl4-(4-(3,5-dichloropyridin-4-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 90AN-(3,5-Dichloropyridin-4-yl)-9-(piperidin-4-yl)-6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-amine,HCl salt

Example 90A was prepared from Example 89 using the same method describedabove for Example 8A. LRMS (ESI): 395.1 [M+H]⁺.

Example 90 iso-Propyl4-(4-(3,5-dichloropyridin-4-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 90 was prepared from Example 90A using the same method describedabove for Example 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.25 (d, J=6.60 Hz,6H) 1.63 (s, 2H) 1.76 (d, J=11.00 Hz, 2H) 2.04-2.18 (m, 2H) 2.87 (s, 2H)3.52-3.60 (m, 2H) 4.24 (t, 2H) 4.36 (t, J=6.60 Hz, 2H) 4.58-4.71 (m, 1H)4.86-4.99 (m, 1H) 6.77 (s, 1H) 7.96 (s, 1H) 8.48 (s, 2H). LRMS (ESI):481.2 [M+H]⁺.

Example 91 4-Methoxyphenyl4-(4-(3,5-dichloropyridin-4-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 91 was prepared from Example 90A using the same method describedabove for Example 31. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.73 (d, J=8.80 Hz,2H) 1.85 (s, 2H) 2.11 (s, 2H) 2.97 (d, 1H) 3.12 (d, 2H) 3.62 (d, J=3.30Hz, 2H) 3.79 (s, 3H) 4.30-4.51 (m, 4H) 4.73 (s, 1H) 6.87 (d, J=9.35 Hz,2H) 7.02 (d, J=9.35 Hz, 2H) 8.00 (s, 1H) 8.49 (s, 2H). LRMS (ESI): 545.2[M+H]⁺.

Example 924-(4-(3,5-Dichloropyridin-4-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)-N,N-diethylpiperidine-1-carboxamide

To triphosgene (20.78 mg, 0.070 mmol) and TEA (0.039 mL, 0.280 mmol) inDCM (0.5 mL) was added 2,2,2-trifluoroethanol (21.02 mg, 0.210 mmol),the reaction mixture was stirred at room temperature for 30 min, thenExample 90A (21 mg, 72% purity, 0.035 mmol) was added. The resultingsolution was stirred at room temperature for 30 minutes. The solvent wasremoved in vacuo. The residue was purified by PREP-HPLC. The fractionwas neutralized with K2CO3, diluted with water and extracted with AcOEt,and the organic layer was dried over MgSO4 and evaporated to yield 14 mg(81%) of Example 92 as a white solid. ¹H NMR (500 MHz, CDCl₃): δ ppm1.12 (t, J=6.87 Hz, 6H) 1.60-1.79 (m, 4H) 2.04-2.14 (m, 2H) 2.83-2.94(m, 2H) 3.20 (q, J=7.15 Hz, 4H) 3.52-3.62 (m, 2H) 3.73 (d, J=13.20 Hz,2H) 4.35 (t, J=6.60 Hz, 2H) 4.61 (s, 1H) 6.78 (s, 1H) 7.96 (s, 1H) 8.47(s, 2H). LRMS (ESI): 494.2 [M+H]⁺.

Example 93N-(3,5-Dichloropyridin-4-yl)-9-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-amine

Example 93 was prepared using the same method described above forExample 32, with the exception that Example 29A was replaced Example90A, and 2-chloropyrimidine was replaced with2-chloro-5-propylpyrimidine. ¹H NMR (500 MHz, CDCl₃): δ ppm 0.93 (t,J=7.15 Hz, 3H) 1.50-1.61 (m, 2H) 1.61-1.77 (m, 2H) 1.85 (d, J=9.90 Hz,2H) 1.99-2.08 (m, 2H) 2.39 (t, J=7.42 Hz, 2H) 2.99 (t, J=11.82 Hz, 2H)3.49-3.61 (m, 2H) 4.36 (t, J=6.32 Hz, 2H) 4.77 (s, 1H) 4.86 (d, J=13.75Hz, 2H) 6.78 (s, 1H) 7.99 (s, 1H) 8.15 (s, 2H) 8.48 (s, 2H). LRMS (ESI):515.2 [M+H]⁺.

Example 94 tert-Butyl4-(4-(2-oxo-1,2-dihydropyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 94 was prepared using the same method described above forExample 83, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 3-aminopyridin-2(1H)-one. ¹H NMR (500 MHz, CDCl₃): δppm 1.48 (s, 9H) 1.68 (s, 2H) 1.76 (d, J=11.00 Hz, 2H) 2.02-2.08 (m, 2H)2.86 (s, 2H) 3.53 (t, J=5.77 Hz, 2H) 4.24 (s, 2H) 4.38 (t, J=6.60 Hz,2H) 4.54-4.72 (m, 1H) 6.30-6.42 (m, 1H) 6.98 (d, J=5.50 Hz, 1H) 8.08 (s,1H) 8.23 (s, 1H) 8.66 (d, J=7.70 Hz, 1H). LRMS (ESI): 443.3 [M+H]⁺.

Example 95 iso-Propyl4-(4-(2-oxo-1,2-dihydropyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 95 was prepared from Example 94 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.21-1.27 (m, 6H) 1.61(s, 2H) 1.76 (d, J=11.00 Hz, 2H) 2.00-2.09 (m, 2H) 2.88 (s, 2H) 3.52 (t,J=5.77 Hz, 2H) 4.25 (t, 2H) 4.36 (t, J=6.32 Hz, 2H) 4.56-4.66 (m, 1H)4.86-4.96 (m, 1H) 6.29-6.38 (m, 1H) 6.94 (d, J=4.95 Hz, 1H) 8.06 (s, 1H)8.22 (s, 1H) 8.64 (d, J=5.50 Hz, 1H). LRMS (ESI): 429.3 [M+H]⁺.

Example 96 tert-Butyl4-(4-(6-cyano-2-methylpyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 96 was prepared using the same method described above forExample 83, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 5-amino-6-methylpicolinonitrile. ¹H NMR (500 MHz,CDCl₃): δ ppm 1.42-1.51 (m, 9H) 1.60 (s, 2H) 1.75 (d, J=11.00 Hz, 2H)2.04-2.20 (m, 2H) 2.57 (s, 3H) 2.84 (s, 2H) 3.55 (t, J=6.05 Hz, 2H) 4.23(s, 2H) 4.38 (t, J=6.60 Hz, 2H) 4.56-4.73 (m, 1H) 7.19 (s, 1H) 7.53 (d,J=8.80 Hz, 1H) 8.06 (s, 1H) 8.97 (d, J=8.25 Hz, 1H). LRMS (ESI): 466.4[M+H]⁺.

Example 97 iso-Propyl4-(4-(6-cyano-2-methylpyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 97 was prepared from Example 96 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.21-1.30 (m, 6H)1.55-1.66 (m, 2H) 1.76 (d, J=10.45 Hz, 2H) 2.04-2.14 (m, 2H) 2.57 (s,3H) 2.87 (s, 2H) 3.55 (t, J=5.77 Hz, 2H) 4.26 (t, 2H) 4.38 (t, J=6.60Hz, 2H) 4.58-4.70 (m, 1H) 4.85-4.99 (m, 1H) 7.20 (s, 1H) 7.53 (d, J=8.80Hz, 1H) 8.06 (s, 1H) 8.96 (d, J=8.80 Hz, 1H). LRMS (ESI): 452.3 [M+H]⁺.

Example 98 tert-Butyl4-(4-(4-methylpyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 98 was prepared using the same method described above forExample 83, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 4-methylpyridin-3-amine. ¹H NMR (500 MHz, CDCl₃): δppm 1.44-1.52 (m, 9H) 1.58-1.66 (m, 2H) 1.77 (d, J=10.45 Hz, 2H)2.01-2.12 (m, 2H) 2.29 (s, 3H) 2.86 (s, 2H) 3.50-3.58 (m, 2H) 4.23 (t,2H) 4.36 (t, J=6.32 Hz, 2H) 4.56-4.71 (m, 1H) 6.65 (s, 1H) 7.13 (d,J=4.95 Hz, 1H) 7.99 (s, 1H) 8.24 (d, J=4.95 Hz, 1H) 9.04 (s, 1H). LRMS(ESI): 441.4 [M+H]⁺.

Example 99 tert-Butyl4-(4-(2-methoxypyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 99 was prepared using the same method described above forExample 83, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 2-methoxypyridin-3-amine. ¹H NMR (500 MHz, CDCl₃): δppm 1.46 (s, 9H) 1.58 (d, J=10.45 Hz, 2H) 1.74 (d, J=10.45 Hz, 2H)1.99-2.13 (m, 2H) 2.84 (s, 2H) 3.52 (t, J=5.77 Hz, 2H) 4.03 (s, 3H)4.13-4.30 (m, 2H) 4.35 (t, J=6.32 Hz, 2H) 4.53-4.68 (m, 1H) 6.88 (dd,J=7.70, 4.95 Hz, 1H) 7.54 (s, 1H) 7.72 (d, J=3.30 Hz, 1H) 8.05 (s, 1H)8.78 (d, J=8.25 Hz, 1H). LRMS (ESI): 457.4 [M+H]⁺.

Example 100 tert-Butyl4-(4-(pyridin-4-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 100 was prepared using the same method described above forExample 83, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with pyridin-4-amine. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.46(s, 9H) 1.57 (d, J=12.10 Hz, 2H) 1.70-1.78 (m, 2H) 1.98-2.14 (m, 2H)2.84 (s, 2H) 3.52 (t, J=5.77 Hz, 2H) 4.20 (t, 2H) 4.33 (t, J=6.60 Hz,2H) 4.56-4.69 (m, 1H) 7.16 (s, 1H) 7.59 (d, J=6.60 Hz, 2H) 8.08 (s, 1H)8.40 (d, J=6.60 Hz, 2H). LRMS (ESI): 427.3 [M+H]⁺.

Example 101 tert-Butyl4-(4-(3-fluoropyridin-4-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 101 was prepared using the same method described above forExample 83, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 3-fluoropyridin-4-amine. ¹H NMR (500 MHz, CDCl₃): δppm 1.47 (s, 9H) 1.58 (d, J=9.90 Hz, 2H) 1.74 (d, J=11.00 Hz, 2H)1.99-2.14 (m, 2H) 2.84 (s, 2H) 3.53 (t, J=5.77 Hz, 2H) 4.22 (s, 2H) 4.35(t, J=6.32 Hz, 2H) 4.56-4.70 (m, 1H) 7.47 (d, J=3.30 Hz, 1H) 8.09 (s,1H) 8.26 (d, J=5.50 Hz, 1H) 8.33 (d, J=2.75 Hz, 1H) 8.63-8.72 (m, 1H).LRMS (ESI): 445.3 [M+H]⁺.

Example 102 iso-Propyl4-(4-(3-fluoropyridin-4-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 102 was prepared from Example 101 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.24 (t, J=6.05 Hz,6H) 1.60 (s, 2H) 1.76 (dd, J=11.55 Hz, 2H) 1.99-2.11 (m, 2H) 2.88 (s,2H) 3.54 (t, J=5.77 Hz, 2H) 4.24 (t, 2H) 4.36 (t, J=6.60 Hz, 2H)4.59-4.70 (m, 1H) 4.85-4.97 (m, 1H) 7.48 (d, J=3.30 Hz, 1H) 8.10 (s, 1H)8.26 (d, J=5.50 Hz, 1H) 8.34 (d, J=2.75 Hz, 1H) 8.62-8.74 (m, 1H). LRMS(ESI): 431.3 [M+H]⁺.

Example 103 tert-Butyl4-(4-(3-chloropyridin-4-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 103 was prepared using the same method described above forExample 83, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 3-chloropyridin-4-amine. ¹H NMR (500 MHz, CDCl₃): δppm 1.43-1.50 (m, 9H) 1.58 (d, J=7.70 Hz, 2H) 1.75 (d, J=10.45 Hz, 2H)2.04-2.16 (m, 2H) 2.85 (d, J=13.20 Hz, 2H) 3.55 (t, J=5.77 Hz, 2H) 4.23(t, 2H) 4.37 (t, J=6.60 Hz, 2H) 4.58-4.70 (m, 1H) 7.89 (s, 1H) 8.10 (s,1H) 8.32 (d, J=5.50 Hz, 1H) 8.43 (s, 1H) 8.70 (d, J=5.50 Hz, 1H). LRMS(ESI): 461.3 [M+H]⁺.

Example 104 iso-Propyl4-(4-(3-chloropyridin-4-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 104 was prepared from Example 103 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.24 (t, J=6.05 Hz,6H) 1.60 (s, 2H) 1.70-1.81 (m, 2H) 2.04-2.17 (m, 2H) 2.87 (s, 2H) 3.54(t, J=5.77 Hz, 2H) 4.24 (t, 2H) 4.37 (t, J=6.60 Hz, 2H) 4.58-4.72 (m,1H) 4.84-5.02 (m, 1H) 7.89 (s, 1H) 8.10 (s, 1H) 8.32 (d, J=5.50 Hz, 1H)8.43 (s, 1H) 8.70 (d, J=5.50 Hz, 1H). LRMS (ESI): 447.2 [M+H]⁺.

Example 105 tert-Butyl4-(4-(3,5-difluoropyridin-4-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 105 was prepared using the same method described above forExample 83, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 3,5-difluoropyridin-4-amine. ¹H NMR (500 MHz, CDCl₃):δ ppm 1.46 (s, 9H) 1.58 (d, J=8.25 Hz, 2H) 1.74 (d, J=10.45 Hz, 2H)1.99-2.14 (m, 2H) 2.83 (s, 2H) 3.54 (t, J=6.05 Hz, 2H) 4.21 (s, 2H) 4.35(t, J=6.32 Hz, 2H) 4.57-4.69 (m, 1H) 6.60 (s, 1H) 7.99 (s, 1H) 8.32 (s,2H). LRMS (ESI): 463.3 [M+H]⁺.

Example 106N-(3,5-difluoropyridin-4-yl)-9-(1-(5-propylpyrimidin-2-yl)piperidin-4-yl)-6,7,8,9-tetrahydropyrimido[5,4-b][1,4]oxazepin-4-amine

Example 106 was prepared from Example 105 using the methods described inExamples 8A and 32. ¹H NMR (500 MHz, CDCl₃): δ ppm 0.93 (t, J=7.42 Hz,3H) 1.57-1.69 (m, 4H) 1.84 (d, J=9.35 Hz, 2H) 1.99-2.10 (m, 2H)2.34-2.45 (m, 2H) 2.90-3.08 (m, 2H) 3.50-3.58 (m, 2H) 4.36 (t, J=6.60Hz, 2H) 4.76 (s, 1H) 4.86 (d, J=13.75 Hz, 2H) 6.61 (s, 1H) 8.02 (s, 1H)8.15 (s, 2H) 8.32 (s, 2H). LRMS (ESI): 483.3 [M+H]⁺.

Example 107 tert-Butyl4-(4-(3-methylpyridin-4-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 107 was prepared using the same method described above forExample 83, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 3-methylpyridin-4-amine. ¹H NMR (500 MHz, CDCl₃): δppm 1.47 (s, 9H) 1.59 (s, 2H) 1.75 (d, J=11.00 Hz, 2H) 1.99-2.13 (m, 2H)2.25 (s, 3H) 2.84 (s, 2H) 3.54 (t, J=6.05 Hz, 2H) 4.22 (s, 2H) 4.36 (t,J=6.60 Hz, 2H) 4.56-4.70 (m, 1H) 7.12 (s, 1H) 8.09 (s, 1H) 8.27 (s, 1H)8.34 (d, J=5.50 Hz, 1H) 8.45 (d, J=6.05 Hz, 1H). LRMS (ESI): 441.3[M+H]⁺.

Example 108 tert-Butyl4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 108 was prepared using the same method described above forExample 83, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 2-methyl-6-(methylsulfonyl)pyridin-3-amine. ¹H NMR(500 MHz, CDCl₃): δ ppm 1.46 (s, 9H) 1.74 (d, J=10.45 Hz, 2H) 2.05-2.18(m, 2H) 2.60 (s, 3H) 2.84 (s, 2H) 3.15 (s, 3H) 3.55 (t, J=5.77 Hz, 2H)4.10 (q, J=7.15 Hz, 2H) 4.23 (t, 2H) 4.38 (t, J=6.60 Hz, 2H) 4.57-4.69(m, 1H) 7.18 (s, 1H) 7.92 (d, J=8.25 Hz, 1H) 8.06 (s, 1H) 9.01 (d,J=8.80 Hz, 1H). LRMS (ESI): 519.3 [M+H]⁺.

Example 109 iso-Propyl4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 109 was prepared from Example 108 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.25 (d, J=6.15 Hz,6H) 1.60 (s, 2H) 1.76 (d, J=10.11 Hz, 2H) 2.02-2.13 (m, 2H) 2.61 (s, 3H)2.79-2.94 (m, 2H) 3.11-3.19 (m, 3H) 3.55 (t, J=5.71 Hz, 2H) 4.38 (t,J=6.37 Hz, 4H) 4.58-4.70 (m, 1H) 4.85-5.00 (m, 1H) 7.18 (s, 1H) 7.92 (d,J=8.79 Hz, 1H) 8.07 (s, 1H) 9.02 (d, J=8.79 Hz, 1H). LRMS (ESI): 505.3[M+H]⁺.

Example 110 iso-Propyl4-(4-(2-chloropyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 110 was prepared from Example 83A using the same methodsdescribed above for Examples 83 and Example 8, with the exception that2-fluoro-4-(methylsulfonyl)aniline was replaced with2-chloropyridin-3-amine ¹H NMR (500 MHz, CDCl₃): δ ppm 1.25 (d, J=6.05Hz, 6H) 1.63 (s, 2H) 1.76 (d, J=11.55 Hz, 2H) 2.01-2.12 (m, 2H)2.80-2.95 (m, 2H) 3.54 (t, J=5.50 Hz, 2H) 4.25 (t, 2H) 4.37 (t, J=6.32Hz, 2H) 4.58-4.69 (m, 1H) 4.85-4.97 (m, 1H) 7.22 (dd, J=7.97, 4.67 Hz,1H) 7.66 (s, 1H) 7.96 (d, J=4.95 Hz, 1H) 8.05 (s, 1H) 9.00 (d, J=8.25Hz, 1H). LRMS (ESI): 447.1 [M+H]⁺.

Example 111 iso-Propyl4-(4-(2-chloro-4-methylpyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 111 was prepared from Example 83A using the same methodsdescribed above for Examples 83 and Example 8, with the exception that2-fluoro-4-(methylsulfonyl)aniline was replaced with2-chloro-4-methylpyridin-3-amine ¹H NMR (500 MHz, CDCl₃): δ ppm 1.25 (d,J=6.60 Hz, 6H) 1.59 (d, J=7.15 Hz, 2H) 1.76 (d, J=12.10 Hz, 2H)2.05-2.14 (m, 2H) 2.33 (s, 3H) 2.86 (s, 2H) 3.50-3.60 (m, 2H) 4.24 (t,2H) 4.36 (t, J=6.60 Hz, 2H) 4.57-4.68 (m, 1H) 4.87-4.98 (m, 1H) 6.59 (s,1H) 7.15 (d, J=4.40 Hz, 1H) 7.90 (s, 1H) 8.12 (d, J=4.95 Hz, 1H). LRMS(ESI): 461.1 [M+H]⁺.

Example 112 tert-Butyl4-(4-(2-methyl-6-(1H-1,2,4-triazol-1-yl)pyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 112 was prepared using the same method described above forExample 83, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 2-methyl-6-(1H-1,2,4-triazol-1-yl)pyridin-3-amine. ¹HNMR (500 MHz, CDCl₃): δ ppm 1.46 (s, 9H) 1.58 (d, J=6.60 Hz, 2H)1.69-1.80 (m, 2H) 2.03-2.12 (m, 2H) 2.55 (s, 3H) 2.84 (s, 2H) 3.54 (t,J=5.77 Hz, 2H) 4.14-4.28 (m, 2H) 4.37 (t, J=6.60 Hz, 2H) 4.56-4.69 (m,1H) 6.88 (s, 1H) 7.71 (d, J=8.80 Hz, 1H) 8.02 (s, 1H) 8.05 (s, 1H) 8.68(d, J=8.80 Hz, 1H) 9.07 (s, 1H). LRMS (ESI): 508.3 [M+H]⁺.

Example 113 iso-Propyl4-(4-(2-methyl-6-(1H-1,2,4-triazol-1-yl)pyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 113 was prepared from Example 112 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.25 (d, J=6.60 Hz,6H) 1.61 (s, 2H) 1.77 (d, J=11.00 Hz, 2H) 2.04-2.12 (m, 2H) 2.55 (s, 3H)2.88 (s, 2H) 3.54 (t, J=5.77 Hz, 2H) 4.26 (t, 2H) 4.37 (t, J=6.60 Hz,2H) 4.64 (s, 1H) 4.86-4.97 (m, 1H) 6.88 (s, 1H) 7.71 (d, J=8.80 Hz, 1H)8.03 (s, 1H) 8.05 (s, 1H) 8.69 (d, J=8.80 Hz, 1H) 9.08 (s, 1H). LRMS(ESI): 494.2 [M+H]⁺.

Example 114 tert-Butyl4-(4-(2-methyl-6-(trifluoromethyl)pyridin-3-ylamino)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 114 was prepared using the same method described above forExample 83, with the exception that 2-fluoro-4-(methylsulfonyl)anilinewas replaced with 2-methyl-6-(trifluoromethyl)pyridin-3-amine. ¹H NMR(500 MHz, CDCl₃): δ ppm 1.47 (s, 9H) 1.58 (d, J=7.15 Hz, 2H) 1.75 (d,J=11.00 Hz, 2H) 2.03-2.12 (m, 2H) 2.59 (s, 3H) 2.84 (s, 2H) 3.54 (t,J=5.77 Hz, 2H) 4.13-4.29 (m, 2H) 4.37 (t, J=6.32 Hz, 2H) 4.56-4.68 (m,1H) 7.07 (s, 1H) 7.51 (d, J=8.80 Hz, 1H) 8.04 (s, 1H) 8.86 (d, J=8.80Hz, 1H). LRMS (ESI): 509.1 [M+H]⁺.

Example 115 tert-Butyl4-(4-(2-methylpyridin-3-yloxy)-7,8-dihydropyrimido[5,4-b][1,4]oxazepin-9(6H)-yl)piperidine-1-carboxylate

Example 115 was prepared using the same method described above forExample 65, with the exception that Example 26A was replaced withExample 83A. ¹H NMR (500 MHz, CDCl₃): δ ppm 1.47 (s, 9H) 1.57-1.66 (m,2H) 1.76 (d, J=10.45 Hz, 2H) 2.04-2.15 (m, 2H) 2.43 (s, 3H) 2.76-2.86(m, 2H) 3.56-3.67 (m, 2H) 4.23 (t, 2H) 4.37 (t, J=6.60 Hz, 2H) 4.64 (s,1H) 7.18 (dd, J=8.25, 4.95 Hz, 1H) 7.37 (d, J=9.35 Hz, 1H) 7.90 (s, 1H)8.36 (d, J=3.30 Hz, 1H). LRMS (ESI): 442.3 [M+H]⁺.

Example 116

Isopropyl4-(4-(2-methylpyridin-3-yloxy)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylate

Example 116A (Z)-Methyl 3-(4,6-dichloropyrimidin-5-yl)acrylate

To a solution of methyl 2-(bis(2,2,2-trifluoroethoxy)phosphoryl)acetate(2.460 mL, 11.63 mmol) in 70 mL of THF at −78° C. was added 18-CROWN-6(9.14 g, 34.6 mmol). Added KHMDS (23.05 mL, 11.53 mmol) dropwise over 15min and allowed the resulting mixture to stir at −78° C. for 30 min.Then 4,6-dichloropyrimidine-5-carbaldehyde (1.7 g, 9.61 mmol) was addedin 20 mL of THF and the resulting mixture was allowed to stir at −78° C.for 1.5 h. The reaction was quenched with about 25 mL sat'd NH4Cl,allowed to warm to RT and then most of the THF was removed by rotaryevaporator. The resulting mixture was diluted with 1:1 hexane/ethylacetate, washed with 1N HCl, sat'd aq sodium bicarbonate and brine,dried (MgSO4), filtered through a pad of silica gel and concentrated invacuo to afford an oil (2.8 g). The residue was purified by silica gelchromatography (80 g ISCO cartridge, 0-80% ethyl acetate/hexane) toafford Example 116A (1.55 g, 69%) as an oil, which was contaminated with˜10% of the (E)-olefin isomer. The material was used without furtherpurification. LRMS (ESI): 233.1 [M+H]⁺.

Example 116B tert-Butyl4-(4-chloro-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylate

To a solution of (Z)-Methyl 3-(4,6-dichloropyrimidin-5-yl)acrylate fromExample 116A (1.2 g, 5.15 mmol) in 40 mL of THF was added tert-butyl4-aminopiperidine-1-carboxylate (1.08 g, 5.41 mmol) and triethylamine(1.08 mL, 7.72 mmol). The resulting mixture was allowed to stir at 65°C. for 18 h. The reaction was cooled, diluted with 1:1 hexane/ethylacetate, washed with 1N HCl, sat'd aq sodium bicarbonate and brine,dried (MgSO4), filtered through a pad of silica gel and concentrated invacuo to afford an oil (1.5 g). The residue was taken up in 15 mL of DMFand then there was added potassium carbonate (1.42 g, 10.3 mmol), andthe reaction mixture was stirred at 100° C. for 1.5 h. The reaction wascooled, diluted with 1:2 hexane/ethyl acetate, washed with water andbrine, dried (MgSO4), filtered through a pad of silica gel andconcentrated in vacuo to afford an oil. The residue was purified bysilica gel chromatography (80 g ISCO cartridge, 0-100% ethylacetate/CH₂Cl₂) to afford Example 116B (0.30 g, 16%) as an off-whitesolid. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.48 (s, 9H) 1.57 (m, 2H) 2.78-2.96(m, 4H) 4.12-4.39 (m, 2H) 5.51-5.63 (m, 1H) 6.77 (d, J=9.90 Hz, 1H) 7.95(d, J=9.35 Hz, 1H) 8.76 (s, 1H). LRMS (ESI): 309.2 [M+H-C4H8]⁺, 265.2[M+H-BOC]⁺.

Example 116C tert-Butyl4-(4-(2-methylpyridin-3-yloxy)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-(4-chloro-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylatefrom Example 116B (76 mg, 0.21 mmol) in 2 mL of DMF was added2-methylpyridin-3-ol (23 mg, 0.21 mmol) and potassium carbonate (58 mg,0.42 mol). The resulting mixture was allowed to stir at 100° C. in asealed vial for 1 h. The reaction mixture was cooled, diluted with ethylacetate, washed with water and brine, dried (MgSO₄), filtered through apad of silica gel and concentrated. The residue was triturated withether to afford 20 mg (21%) of Example 116C as a pale yellow solid. ¹HNMR (500 MHz, CDCl₃) δ 1.47 (s, 9H) 1.57-1.64 (m, 2H) 2.42 (s, 3H)2.74-2.99 (m, 4H) 4.10-4.38 (m, 2H) 5.54-5.67 (m, 1H) 6.74 (d, J=9.90Hz, 1H) 7.26 (dd, J=8.25, 4.95 Hz, 1H) 7.45 (d, J=8.25 Hz, 1H) 8.07 (d,J=9.90 Hz, 1H) 8.47 (d, J=3.30 Hz, 1H) 8.50 (s, 1H). LRMS (ESI): 438.3[M+H]⁺.

Example 116 Isopropyl4-(4-(2-methylpyridin-3-yloxy)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylate

To a solution of tert-butyl4-(4-(2-methylpyridin-3-yloxy)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylatefrom Example 116C (56 mg, 0.13 mmol) in 4 mL methylene chloride wasadded 4 mL of trifluoroacetic acid. The resulting mixture was stirred atroom temperature for 1 h and then was concentrated in vacuo. The residuewas taken up in 4 mL of methylene chloride and then there was addedtriethylamine (0.054 mL, 0.38 mmol) and isopropylchloroformate (0.13 mLof a 1M solution in toluene, 0.13 mmol). The resulting mixture wasallowed to stir at room temperature for 18 h. The reaction was dilutedwith ethyl acetate, washed with sat'd aq sodium bicarbonate and brine,dried (MgSO4), filtered through a pad of silica gel and concentrated.The residue was purified by silica gel chromatography (12 g ISCOcartridge, 0-100% ethyl acetate/hexane) to afford 28 mg (49%) of Example116 as an off-white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.21 (d, J=6.05Hz, 6H) 1.55-1.61 (m, 2H) 2.37 (s, 3H) 2.80-2.93 (m, 4H) 4.20-4.36 (m,2H) 4.85-4.92 (m, 1H) 5.57 (s, 1H) 6.70 (d, J=9.35 Hz, 1H) 7.21 (dd,J=7.97, 4.67 Hz, 1H) 7.40 (d, J=6.60 Hz, 1H) 8.02 (d, J=9.35 Hz, 1H)8.42 (d, J=4.95 Hz, 1H) 8.46 (s, 1H). LRMS (ESI): 424.3 [M+H]⁺.

Example 117

Isopropyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylate

By the procedures described in Example 3 and Example 116, tert-butyl4-(4-chloro-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylatefrom Example 116B was converted in Example 117. ¹H NMR (500 MHz, CDCl₃)δ ppm 1.21 (d, J=5.50 Hz, 6H) 1.53-1.59 (m, 2H) 2.79-2.95 (m, 4H) 3.02(s, 3H) 4.20-4.36 (m, 2H) 4.86-4.92 (m, 1H) 5.54-5.69 (m, 1H) 6.68 (d,J=9.35 Hz, 1H) 7.45 (d, J=3.30 Hz, 1H) 7.66-7.70 (m, 2H) 7.73 (d, J=8.80Hz, 1H) 8.61 (s, 1H) 8.71-8.76 (m, 1H). LRMS (ESI): 504.2 [M+H]⁺.

Example 118

Isopropyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-7-oxo-6,7-dihydropyrido[2,3-d]pyrimidin-8(5H)-yl)piperidine-1-carboxylate

To a solution of isopropyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)piperidine-1-carboxylatefrom Example 117 (53 mg, 0.105 mmol) in ethanol (10 mL) was added 20%Pd(OH)₂/C (20 mg, 0.057 mmol). Using a three-way stopcock, the reactionmixture was alternately evacuated and purged with hydrogen from aballoon several times. The reaction mixture was then allowed to stirunder 1 atm of H2 at ambient temperature for 18 h. The mixture wasfiltered through pad of CELITE® 545 filter aid and concentrated to anoil. The residue was purified by flash chromatography (12 g ISCO column,elution with 0-100% ethyl acetate/hexane) to afford 5 mg (9%) of Example118 as an off white solid. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.25 (d, J=5.50Hz, 6H) 1.54-1.61 (m, 4H) 2.65-2.81 (m, 6H) 3.05 (s, 3H) 4.18-4.32 (m,2H), 4.87-4.95 (m, 1H) 5.02-5.09 (m, 1H) 6.83 (s, 1H) 7.69 (d, J=10.45Hz, 1H) 7.74 (d, J=8.80 Hz, 1H) 8.53 (s, 1H) 8.76-8.81 (m, 1H). LRMS(ESI): 506.2 [M+H]⁺.

Example 119 Isopropyl4-(4-(2-chloro-4-(oxazol-5-yl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 119A 2-Chloro-4-(oxazol-5-yl)aniline

To a solution of 4-(oxazol-5-yl)aniline (1.2 g, 7.49 mmol) in 25 mL ofacetonitrile was added N-chlorosuccinimide (1.25 g, 9.36 mmol) as asolution in 15 mL of acetonitrile. The resulting mixture was stirred atreflux for 4 h. The mixture was cooled, diluted with ethyl acetate,washed with water, sat'd aq sodium bicarbonate (2×) and brine, dried(MgSO4), filtered through a pad of silica gel and concentrated. Theresidue was purified by silica gel chromatography (40 g ISCO cartridge,0-100% ethyl acetate/hexane) to afford 0.53 g (36%) of Example 119A as ayellow solid. LRMS (ESI): 195.1/197.1 [M+H]⁺.

Example 119 Isopropyl4-(4-(2-chloro-4-(oxazol-5-yl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

By the procedure described in Example 3, with the exception that Example119A was used instead of 2-fluoro-4-(methylsulfonyl)aniline, isopropyl4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylatefrom Example 20A was converted into Example 119. ¹H NMR (500 MHz, CDCl₃)δ ppm 1.27 (d, J=6.05 Hz, 6H) 1.59-1.76 (m, 4H) 2.88-2.98 (m, 2H)3.46-3.49 (m, 2H) 4.28-4.31 (m, 4H) 4.83-4.90 (m, 1H) 4.90-4.97 (m, 1H)7.29 (s, 1H) 7.44 (s, 1H) 7.55 (dd, J=8.80, 2.20 Hz, 1H) 7.68 (d, J=2.20Hz, 1H) 7.90 (s, 1H) 8.10 (s, 1H) 8.73 (d, J=8.80 Hz, 1H). LRMS (ESI):499.2/501.2 [M+H]⁺.

Example 120 Isopropyl4-(4-(3-chloropyridin-4-ylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

By the procedure described in Example 3, with the exception that3-chloro-4-aminopyridine was used instead of2-fluoro-4-(methylsulfonyl)aniline, isopropyl4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylatefrom Example 20A was converted into Example 120. ¹H NMR (500 MHz, CDCl₃)δ ppm 1.24 (d, J=6.60 Hz, 6H) 1.59-1.64 (m, 2H) 1.66-1.74 (m, 2H)2.85-2.93 (m, 2H) 3.44-3.47 (m, 2H) 4.25-4.29 (m, 4H) 4.80-4.87 (m, 1H)4.87-4.94 (m, 1H) 7.60 (s, 1H) 8.09 (s, 1H) 8.31 (d, J=6.05 Hz, 1H) 8.44(s, 1H) 8.75 (d, J=5.50 Hz, 1H). LRMS (ESI): 433.3/435.2 [M+H]⁺.

Example 121 Isopropyl4-(4-(3-fluoropyridin-4-ylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

By the procedure described in Example 3, with the exception that3-fluoro-4-aminopyridine was used instead of2-fluoro-4-(methylsulfonyl)aniline, isopropyl4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylatefrom Example 20A was converted into Example 121. ¹H NMR (500 MHz, CDCl₃)δ ppm 1.23 (d, J=6.60 Hz, 6H) 1.62 (s, 2H) 1.66-1.73 (m, 2H) 2.84-2.93(m, 2H) 3.43-3.46 (m, 2H) 4.23-4.31 (m, 4H) 4.79-4.87 (m, 1H) 4.87-4.94(m, 1H) 7.19 (d, J=3.30 Hz, 1H) 8.08 (s, 1H) 8.25 (d, J=6.05 Hz, 1H)8.33 (d, J=2.20 Hz, 1H) 8.65-8.70 (m, 1H). LRMS (ESI): 417.2 [M+H]⁺.

Example 122 Isopropyl4-(4-(3-(trifluoromethyl)pyridin-4-ylamino)-6H-pyrimido[5][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

By the procedure described in Example 3, with the exception that3-trifluoromethyl-4-aminopyridine was used instead of2-fluoro-4-(methylsulfonyl)aniline, isopropyl4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylatefrom Example 20A was converted into Example 122. ¹H NMR (500 MHz, CDCl₃)δ ppm 1.19 (d, J=6.60 Hz, 6H) 1.53-1.61 (m, 2H) 1.62-1.69 (m, 2H)2.79-2.89 (m, 2H) 3.40-3.43 (m, 2H) 4.21-4.25 (m, 4H) 4.76-4.82 (m, 1H)4.82-4.89 (m, 1H) 7.57 (broad s, 1H) 8.05 (s, 1H) 8.47-8.51 (m, 1H) 8.62(broad s, 1H) 8.86 (d, J=5.50 Hz, 1H). LRMS (ESI): 467.3 [M+H]⁺.

Example 123 tert-Butyl4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

By the procedure described in Example 3, with the exception that2-methyl-6-(methylsulfonyl)pyridin-3-amine was used instead of2-fluoro-4-(methylsulfonyl)-aniline, tert-butyl4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylatefrom Example 3C was converted into Example 123. ¹H NMR (500 MHz, CDCl₃)δ ppm 1.45 (s, 9H) 1.55-1.65 (m, 2H) 1.66-1.72 (m, 2H) 2.61 (s, 3H)2.82-2.90 (m, 2H) 3.15 (s, 3H) 3.45-3.48 (m, 2H) 4.25-4.28 (m, 4H)4.79-4.88 (m, 1H) 6.86-7.00 (m, 1H) 7.91 (d, J=8.25 Hz, 1H) 8.06 (s, 1H)8.91 (m, 1H). LRMS (ESI): 505.3 [M+H]⁺.

Example 124 Isopropyl4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 124 was prepared from Example 123 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CD3OD) δ ppm 1.26 (d, J=6.60 Hz, 6H)1.69-1.76 (m, 4H) 2.59 (s, 3H) 2.86-2.99 (m, 2H) 3.19 (s, 3H) 3.54-3.57(m, 2H) 4.23-4.31 (m, 4H) 4.84-4.87 (m, 2H) 7.88-7.91 (m, 2H) 8.54 (d,J=8.25 Hz, 1H). LRMS (ESI): 491.2 [M+H]⁺.

Example 125 Isopropyl4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 125A Isopropyl4-(4-chloro-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 125A was prepared from Example 26A following the proceduresdescribed in Example 116. LRMS (ESI): 355.1 [M+H]⁺.

Example 125 Isopropyl4-(4-(2-methyl-6-(methylsulfonyl)pyridin-3-ylamino)-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

To a solution of isopropyl4-(4-chloro-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylatefrom Example 125A (33 mg, 0.093 mmol) in degassed toluene (2 mL) wasadded 2-methyl-6-(methylsulfonyl)pyridin-3-amine (17.32 mg, 0.093 mmol),Cs₂CO₃ (42.4 mg, 0.130 mmol), Xantphos (8.07 mg, 0.014 mmol) andPd₂(dba)₃ (8.52 mg, 9.30 mmol). Purged for 2 min with stream of argon,stirred in sealed vial at 110° C. for 18 h. The reaction was cooled,diluted with ethyl acetate, washed with brine, dried (MgSO4), filteredthrough a pad of silica gel and concentrated in vacuo to afford an oil.The residue was purified by silica gel chromatography (12 g ISCOcartridge, 0-80% ethyl acetate/hexane) to afford 8 mg (17%) of Example125 as a pale yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.00(1H, d, J=8.35 Hz), 8.29 (1H, s), 7.96 (1H, d, J=8.35 Hz), 6.97 (1H, s),4.96-5.06 (1H, m), 4.93 (1H, quin, J=6.15 Hz), 4.76 (2H, s), 4.19-4.41(2H, m), 3.18 (3H, s), 2.75-2.89 (2H, m), 2.65-2.75 (2H, m), 2.64 (3H,s), 1.61-1.69 (2H, m), 1.25 (6H, d, J=5.71 Hz). LRMS (ESI): 505.1[M+H]⁺.

Example 126 Isopropyl4-(4-(2-methyl-6-(1H-1,2,4-triazol-1-yl)pyridin-3-ylamino)-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 126 was prepared from Example 125A following the proceduredescribed in Example 125, with the exception that2-methyl-6-(1H-1,2,4-triazol-1-yl)pyridin-3-amine was used instead of2-methyl-6-(methylsulfonyl)pyridin-3-amine. ¹H NMR (500 MHz,CHLOROFORM-d) δ ppm 9.10 (1H, s), 8.60 (1H, d, J=8.25 Hz), 8.22 (1H, s),8.06 (1H, s), 7.76 (1H, d, J=8.80 Hz), 6.71 (1H, s), 4.96-5.04 (1H, m),4.89-4.96 (1H, m), 4.73 (2H, s), 4.20-4.40 (2H, m), 2.76-2.88 (2H, m),2.69 (2H, qd, J=12.28, 4.40 Hz), 2.57 (3H, s), 1.62-1.69 (2H, m), 1.25(6H, d, J=6.05 Hz). LRMS (ESI): 494.1 [M+H]⁺.

Example 127 Isopropyl4-(4-(2-chloropyridin-3-ylamino)-7-oxo-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 126 was prepared from Example 125A following the proceduredescribed in Example 125, with the exception that2-chloropyridin-3-amine was used instead of2-methyl-6-(methylsulfonyl)pyridin-3-amine ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 9.00 (1H, dd, J=8.13, 1.54 Hz), 8.26 (1H, s), 8.05(1H, dd, J=4.61, 1.54 Hz), 7.50 (1H, s), 7.27 (1H, dd, J=8.13, 4.61 Hz),4.95-5.04 (1H, m), 4.89-4.95 (1H, m), 4.75 (2H, s), 4.21-4.40 (2H, m),2.75-2.88 (2H, m), 2.62-2.75 (2H, m), 1.60-1.69 (2H, m), 1.25 (6H, d,J=6.15 Hz). LRMS (ESI): 447.2/449.2 [M+H]⁺.

Examples 128 to 138

Examples 128 to 138 were prepared from isopropyl4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylatefrom Example 20A in library format by the following procedure. Therequired aniline reagents (1.0 eq) were weighed directly into 0.5-2 mLBIOTAGE microwave vials. Isopropyl4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylatefrom Example 20A (688 mg, 2.02 mmol, 1 eq) was dissolved in 20.2 mL oftoluene and agitated. To this core solution was added BINAP (59 mg, 0.06eq) and NaOt-Bu (192 mg, 1.0 eq). To each reagent vial was added 1.0 mLcore solution. Pd₂(dba)₂ (approx. 4 mg, 0.04 eq) was added to each vial.Reactions were heated to 130° C. for 15 minutes in the microwave. Thereactions were concentrated, the residues redissolved in 1 mL DMF, andfiltered through a 0.45 micron syringe filter. They were purified usingpreparative LCMS.

Example 128 Isopropyl4-(4-(4-methoxyphenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

LRMS (ESI): 428.1 [M+H]⁺.

Example 129 Isopropyl4-(4-(4-(oxazol-5-yl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

LRMS (ESI): 465.1 [M+H]⁺.

Example 130 Isopropyl4-(4-(4-(pyrrolidine-1-carbonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

LRMS (ESI): 495.3 [M+H]⁺.

Example 131 Isopropyl4-(4-(4-(1H-pyrazol-1-yl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

LRMS (ESI): 464.2 [M+H]⁺.

Example 132 Isopropyl4-(4-(benzo[d][1,3]dioxol-5-ylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

LRMS (ESI): 442.2 [M+H]⁺.

Example 133 Isopropyl4-(4-(4-(methoxycarbonyl)-2-methylphenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

LRMS (ESI): 470.2 [M+H]⁺.

Example 134 Isopropyl4-(4-(4-cyano-2-methylphenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

LRMS (ESI): 437.2 [M+H]⁺.

Example 135 Isopropyl4-(4-(4-methoxy-2-methylphenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

LRMS (ESI): 442.2 [M+H]⁺.

Example 136 Isopropyl4-(4-(2,6-difluorophenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

LRMS (ESI): 434.1 [M+H]⁺.

Example 137 Isopropyl4-(4-(2-chloro-5-cyanophenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

LRMS (ESI): 457/459 [M+H]⁺.

Example 138 Isopropyl4-(4-(3-(methoxycarbonyl)-2-methylphenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

LRMS (ESI): 470.2 [M+H]⁺.

Example 139N-(2-Fluoro-4-(methylsulfonyl)phenyl)-8-(1-(5-methylbenzo[d]oxazol-2-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine

Example 139 was prepared from Example 8A following the proceduredescribed in Example 17, except that 2-chlorobenzo[d]oxazole wasreplaced with 2-chloro-5-methylbenzo[d]oxazole. ¹H NMR (400 MHz, CDCl₃)δ ppm 8.89 (t, J=8.1 Hz, 1H) 8.10 (s, 1H) 7.67-7.75 (m, 1H) 7.64 (dd,J=10.3, 2.0 Hz, 1H) 7.25 (s, 1H) 7.19-7.24 (m, 1H) 7.14 (d, J=8.4 Hz,1H) 6.86 (d, J=7.5 Hz, 2H) 4.91-5.03 (m, 1H) 4.51 (d, J=12.7 Hz, 2H)4.22-4.31 (m, 2H) 3.42-3.50 (m, 2H) 3.23-3.36 (m, 2H) 3.03 (s, 3H) 2.39(s, 3H) 1.83-1.93 (m, 3H)

Example 140N-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(1-(4-methylpyrimidin-2-yl)piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine

Example 140 was prepared from Example 8A following a procedure similarto that described in Example 17, except that 2-chlorobenzo[d]oxazole wasreplaced with 2-chloro-4-methylpyrimidine. ¹H NMR (400 MHz, CDCl₃) δ ppm8.90 (t, J=8.1 Hz, 1H) 8.20 (d, J=5.3 Hz, 1H) 8.11 (s, 1H) 7.70 (d,J=8.8 Hz, 1H) 7.62-7.68 (m, 1H) 7.24 (d, J=4.0 Hz, 1H) 6.46 (d, J=4.8Hz, 1H) 4.93-5.13 (m, 3H) 4.21-4.30 (m, 2H) 3.42-3.48 (m, 2H) 3.05-3.16(m, 2H) 3.04 (s, 3H) 2.38-2.49 (m, 3H) 1.86 (d, J=11.0 Hz, 2H) 1.65-1.80(m, 2H).

Example 1418-(1-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)-N-(2-fluoro-4-(methylsulfonyl)phenyl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine

Example 141 was prepared from Example 8A following a procedure similarto that described in Example 17, except that 2-chlorobenzo[d]oxazole wasreplaced with 2-chloro-5-ethylpyrimidine. ¹H NMR (400 MHz, CDCl₃) δ ppm8.88 (t, J=8.4 Hz, 1H) 8.22 (s, 2H) 8.10 (s, 1H) 7.69 (d, J=8.8 Hz, 1H)7.63 (dd, J=10.6, 1.8 Hz, 1H) 7.22 (d, J=4.4 Hz, 1H) 4.86-5.02 (m, 3H)4.21-4.27 (m, 2H) 3.40-3.48 (m, 2H) 3.03-3.15 (m, 2H) 3.03 (s, 3H) 2.49(q, J=7.8 Hz, 2H) 1.78-1.87 (m, 2H) 1.62-1.77 (m, 2H) 1.20 (t, J=7.8 Hz,3H).

Example 142 1,1,1-Trifluoropropan-2-yl4-(4-(4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate,TFA salt

Example 142A 1,1,1-Trifluoropropan-2-yl chloroformate

To a mixture of 1,1,1-trifluoro-2-propanol (114.1 mg, 1.0 mmol, MatrixScientific) and triphosgene (98 mg, 0.33 mmol, Aldrich) in ethyl ether(10 mL) at −40° C. was added pyridine (80 μL, 1.0 mmol, EMD) in ethylether (1.0 mL) dropwise. The reaction mixture was warmed to 0° C. andstirred for 6 h. The flask containing the above reaction mixture was putinto a refrigerator overnight and then filtered. The filtrate wasconcentrated in vacuo in ice both to give a colorless oil which was useddirectly in the next step.

Example 142 1,1,1-Trifluoropropan-2-yl4-(4-(4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

To a suspension ofN-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-aminehydrochloric acid salt from Example 8A (35.5 mg, 0.08 mmol) in CH₂Cl₂(1.5 mL) was added DIEP (70 μL, 0.40 mmol, Aldrich) followed by additionof 1,1,1-trifluoropropan-2-ylchloroformate (⅓ of the material from StepA, 0.33 mmol) in CH₂Cl₂ (0.5 mL). The reaction mixture was stirred for30 min and then evaporated under the reduced pressure to yield the crudeproduct which was purified by preparative HPLC (C₁₈ column; 10-100%acetonitrile in water containing 0.05% trifluoroacetic acid) to give thedesired product (33.9 mg, off-white solid, 51%) upon lyophilization. ¹HNMR (500 MHz, CDCl₃, 50° C.). δ 8.42 (t, J=8.25 Hz, 1H), 8.31 (brs, 1H),8.14 (s, 1H), 7.59-7.78 (m, 2H), 5.18-5.34 (m, 1H), 4.78-4.93 (m, 1H),4.22-4.41 (m, 4H), 3.47-3.55 (m, 2H), 3.04 (s, 3H), 2.88-3.07 (m, 2H),1.79 (m, 2H), 1.60-1.75 (m, 2H), 1.42 (d, J=6.60 Hz, 3H). LRMS (ESI) 548(M+H)+.

Example 143 1,1,1-Trifluoro-2-methylpropan-2-yl4-(4-(4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 143 was prepared according to procedures described in Example142 with substitution of 2-(trifluoromethyl)propan-2-ol for1,1,1-trifluoro-2-propanol.

The title compound was purified by flash chromatography on silica gel(0-100% EtOAc/hexane). ¹H NMR (500 MHz, CDCl₃). δ 8.87-8.94 (m, 1H),8.10 (s, 1H), 7.71 (d, J=8.80 Hz, 1H), 7.66 (dd, J=10.45, 2.20 Hz, 1H),7.23 (d, J=4.40 Hz, 1H), 4.79-4.94 (m, 1H), 4.22-4.37 (m, 3H), 4.09-4.22(m, 1H), 3.43-3.52 (m, 2H), 3.05 (s, 3H), 2.83-3.04 (m, 2H), 1.61-1.81(m, 10H). LRMS (ESI) 562 (M+H)+.

Example 144 1,3-Difluoro-2-methylpropan-2-yl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 144 was prepared according to procedures described in Example142 with substitution of 1,3-difluoro-2-methylpropan-2-ol for1,1,1-trifluoro-2-propanol. The title compound was purified by flashchromatography on silica gel (0-100% EtOAc/hexane). ¹H NMR (500 MHz,CDCl₃). δ 8.90 (t, J=8.52 Hz, 1H), 8.09 (s, 1H), 7.71 (d, J=8.80 Hz,1H), 7.66 (dd, J=10.45, 2.20 Hz, 1H), 7.23 (d, J=3.85 Hz, 1H), 4.78-4.92(m, 1H), 4.67-4.79 (m, 1H), 4.63 (d, J=7.70 Hz, 1H), 4.54 (d, J=7.70 Hz,1H), 4.14-4.33 (m, 4H), 2.83-3.08 (m, 2H), 1.60-1.80 (m, 4H), 1.55 (d,J=15.40 Hz, 3H). LRMS (ESI) 544 (M+H)+.

Example 145 2,2,2-Trifluoroethyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate,TFA salt

Example 145 was prepared according to procedures described in Example142 with substitution of 2,2,2-trifluoroethanol for1,1,1-trifluoro-2-propanol. ¹H NMR (500 MHz, CDCl₃). δ 1H NMR (500 MHz,CDCl₃) δ 8.95 (brs, 1H), 8.19-8.29 (m, 1H), 8.15 (s, 1H), 7.63-7.75 (m,2H), 4.81-4.96 (m, 1H), 4.51-4.62 (m, 1H), 4.41-4.51 (m, 1H), 4.33-4.41(m, 1H), 4.24-4.33 (m, 1H), 4.21 (t, J=4.40 Hz, 2H), 3.52 (t, J=4.40 Hz,2H), 3.07 (s, 1H), 2.82-3.11 (m, 2H), 1.78-1.86 (m, 2H), 1.70 (s, 2H).LRMS (ESI) 534 (M+H)+.

Example 146 (±)-sec-Butyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate,TFA salt

Example 146 was prepared according to procedures described in Example142 with substitution of (f)-2-butanol for 1,1,1-trifluoro-2-propanol.¹H NMR (500 MHz, CDCl₃). δ 9.05 (brs, 1H), 8.19 (t, J=7.97 Hz, 1H), 8.14(s, 1H), 7.64-7.74 (m, 2H), 4.81-4.92 (m, 1H), 4.71-4.81 (m, 1H), 4.33(app brs, 2H), 4.19 (t, J=4.40 Hz, 2H), 3.52 (t, J=4.40 Hz, 2H), 3.07(s, 3H), 2.85-2.99 (m, 2H), 1.72-1.83 (m, 2H), 1.50-1.72 (m, 4H), 1.24(d, J=6.60 Hz, 3H), 0.92 (t, J=7.42 Hz, 3H). LRMS (ESI) 508 (M+H)+.

Example 147 1-Methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate,TFA salt

Example 147 was prepared according to procedures described in Example142 with substitution of 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-olfor 1,1,1-trifluoro-2-propanol. ¹H NMR (500 MHz, CDCl₃). δ 9.13 (brs,1H), 8.11-8.22 (m, 2H), 7.70 (dd, J=15.40, 9.35 Hz, 2H), 6.49 (s, 1H),4.84-4.98 (m, 1H), 4.37-4.52 (m, 2H), 4.21 (t, J=4.40 Hz, 2H), −3.92 (s,3H), 3.55 (t, J=4.40 Hz, 2H), 3.17 (m, 1H), 3.07 (s, 3H), 2.99-3.09 (m,1H), 1.73-1.89 (m, 4H). LRMS (ESI) 600 (M+H)+.

Example 148 Isopropyl4-(4-(4-cyano-2-fluorophenoxy)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

To a solution of isopropyl4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylatefrom Example 20A (10.0 mg, 0.029 mmol) and3-fluoro-4-hydroxybenzonitrile (12.07 mg, 0.088 mmol) in DMF (0.4 mL)was added K2CO3 (12.17 mg, 0.088 mmol). The reaction mixture was stirredin a sealed vial for 3 days at 120° C. The reaction mixture was cooledto RT. The reaction mixture was diluted with MeOH, filtered and purifiedby reverse phase HPLC (H₂O/CH₃CN) to give isopropyl4-(4-(4-cyano-2-fluorophenoxy)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate(1.0 mg, 2.265 μmol, 7.72% yield) as Example 148 as an off-white solid.¹H NMR (400 MHz, CDCl₃) δ ppm 1.27 (d, J=6.05 Hz, 6H) 1.55-1.79 (m, 4H)2.85-2.95 (m, 2H) 3.44-3.54 (m, 2H) 4.05-4.15 (m, 2H) 4.24-4.35 (m, 2H)4.84-4.95 (m, 2H) 7.29-7.40 (m, 1H) 7.45-7.52 (m, 2H) 7.88 (s, 1H). LRMS(ESI): 442.5 [M+H]⁺.

Example 149 3-Methoxyphenyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate,TFA salt

Example 149A 3-Methoxyphenyl 4-nitrophenyl carbonate

To a solution of 3-methoxyphenol (0.11 mL, 1.0 mmol) in CH₂Cl₂ (4.0 mL)was added DIEA (0.21 mL, 1.2 mmol) followed by addition of 4-nitrophenylchloroformate (241.8 mg, 1.2 mmol). The reaction mixture was stirred atroom temperature for 30 min, diluted with CH₂Cl₂ and washed withsaturated NaHCO₃ solution, saturated NH₄Cl solution and brine. Theorganic layer was dried (MgSO₄) and evaporated under the reducedpressure to give the desired product (0.294 g) as a yellow solid whichwas used directly in the next step. MS (ESI) 290 (M+H)+.

Example 149 3-Methoxyphenyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate,TFA salt

To a suspension ofN-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-aminehydrochloric acid salt from Example 8A (35.5 mg, 0.08 mmol) in CH₂Cl₂(2.0 mL) was added DIEA (42 μL, 0.24 mmol, Aldrich) followed by additionof 3-methoxyphenyl 4-nitrophenyl carbonate from Example 149A (27.8 mg,0.096 mmol). The reaction mixture was stirred for 2 hrs, diluted withCH₂Cl₂ and washed with 0.5N NaOH aqueous solution and brine. The organiclayer was dried (Na₂SO₄) and evaporated under the reduced pressure toyield the crude product which was purified by preparative HPLC (C₁₈column; 0-100% acetonitrile in water containing 0.05% trifluoroaceticacid) to give Example 149 (22.6 mg, off-white solid, 50%) uponlyophilization. ¹H NMR (500 MHz, CDCl₃). δ ppm 8.75 (brs, 1H), 8.27-8.41(m, 1H), 8.15 (s, 1H), 7.61-7.80 (m, 2H), 7.19-7.37 (m, 1H), 6.77 (dd,J=8.25, 2.20 Hz, 1H), 6.71 (d, J=7.15 Hz, 1H), 6.68 (d, J=2.20 Hz, 1H),4.87-4.98 (m, 1H), 4.46 (app brs, 2H), 4.24 (t, J=4.12 Hz, 2H), 3.80 (s,3H), 3.56 (t, J=4.12 Hz, 2H), 3.12-3.23 (m, 1H), 3.07 (s, 3H), 2.97-3.12(m, 1H), 1.71-1.92 (m, 4H). LRMS (ESI) 558 (M+H)+.

Example 150 tert-Butyl4-(4-(2,4-dichloropyridin-3-ylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

To 2,4-dichloropyridin-3-amine (19.20 mg, 0.118 mmol) in DMF (1.5 mL)was added NaH (4.28 mg, 0.107 mmol), the reaction was stirred at roomtemperature for 30 minutes, then tert-butyl4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylatefrom Example 3C (38 mg, 0.107 mmol) was added and the reaction mixturewas heated under microwave irradiation at 140° C. for 60 minutes. Noreaction. An additional 2 eq of NaH was added, and the reaction mixturewas heated under microwave irradiation at 140° C. for 60 minutes. Thereaction was filtered through a pad of silica gel, concentrated, andpurified by a silica gel flash column, eluted by 0-50% EtOAc/Hexane toafford Example 150 (6 mg, 0.012 mmol, 11.06% yield) as a pale solid. ¹HNMR (500 MHz, CDCl₃) δ ppm 1.47 (s, 9H) 1.62 (d, J=15.95 Hz, 2H) 1.69(s, 2H) 2.86 (s, 2H) 3.42-3.51 (m, 2H) 4.14-4.31 (m, 4H) 4.74-4.87 (m,1H) 6.28 (s, 1H) 7.36 (d, J=4.95 Hz, 1H) 7.92 (s, 1H) 8.16 (d, J=5.50Hz, 1H). LRMS (ESI) 481.1 (M+H)+.

Example 151 tert-Butyl4-(4-(2,6-dichloropyridin-3-ylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 151 was prepared from Example 3C by the procedure described inExample 150, with the exception that 2,4-dichloropyridin-3-amine wasreplaced by 2,6-dichloropyridin-3-amine ¹H NMR (500 MHz, CDCl₃) δ ppm1.47 (s, 9H) 1.57-1.63 (m, 2H) 1.68 (s, 2H) 2.86 (s, 2H) 3.42-3.49 (m,2H) 4.16-4.33 (m, 4H) 4.75-4.87 (m, 1H) 7.23-7.28 (m, 2H) 8.03 (s, 1H)9.05 (d, J=8.80 Hz, 1H). LRMS (ESI) 481.1 (M+H)+.

Example 152 tert-Butyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-methyl-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 152A 5-Methoxy-2-methylpyrimidine-4,6-diol

MeOH (100 mL) was added with ice bath cooling to Sodium tert-butoxide(12.22 g, 127 mmol). When the mixture had cooled to less than 20° C.,dimethyl 2-methoxymalonate (8.25 g, 50.9 mmol) was added, and then solidacetamidamide, HCl (4.81 g, 50.9 mmol) was added, the mixture wasstirred in the ice bath for 30 minutes and then refluxed for 1 hour. Themixture was cooled in a cold water bath and then concentrated HCl (about35 ml) was added until the mixture was strongly acidic on pH test paper.The precipitate was filtered, suspended in cold water (about 50 ml), andthen filtered again. The white powder was dried in vacuo and carried onwithout further purification (7.22 g, 46.2 mmol, 91% yield). ¹H NMR (500MHz, CD₃OD): δ 2.33 (s, 3H), 3.72 (s, 3H). LRMS (ESI): 157.1 [M+H]⁺.

Example 152B 4,6-Dichloro-5-methoxy-2-methylpyrimidine

The mixture of Example 152A (3.80 g, 24.34 mmol) and N,N-Diethylaniline(1.5 mL, 24.34 mmol) in POCl₃ (20 ml, 215 mmol) was heated undermicrowave irradiation at 100° C. for 60 minutes. The reaction wasfiltered and the liquid was concentrated in vacuo. The residue waspurified by a silica gel flash column and eluted by 0-30% EtOAc/Hexaneto afford Example 152B (2.24 g, 11.60 mmol, 47.7% yield) as aneedle-like crystal. ¹H NMR (500 MHz, CD₃OD): δ 2.63 (s, 3H), 3.92 (s,3H). LRMS (ESI): 193/195 [M+H]⁺.

Example 152C tert-Butyl4-(6-chloro-5-methoxy-2-methylpyrimidin-4-ylamino)piperidine-1-carboxylate

Example 152C was prepared using the same method described above forExample 3A, with the exception that 4,6-dichloro-5-methoxypyrimidine wasreplaced with Example 152B. ¹H NMR (500 MHz, CDCl₃): δ 1.43 (s, 9H)1.90-2.04 (m, 2H) 2.41 (s, 3H) 2.89 (s, 2H) 3.77 (s, 3H) 3.98-4.16 (m,4H) 5.15 (d, J=8.25 Hz, 1H). LRMS (ESI): 357.1 [M+H]⁺.

Example 152D tert-Butyl4-(6-chloro-5-hydroxy-2-methylpyrimidin-4-ylamino)piperidine-1-carboxylate

Example 152D was prepared using the same method described above forExample 3B, with the exception that Example 3A was replaced with Example152C. LRMS (ESI): 343.1 [M+H]⁺.

Example 152E tert-Butyl4-(4-chloro-2-methyl-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 152E was prepared using the same method described above forExample 3C, with the exception that Example 3B was replaced with Example152D. LRMS (ESI): 369.1 [M+H]⁺.

Example 152 tert-Butyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-methyl-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 152 was prepared using the same method described above forExample 3, with the exception that Example 3C was replaced with Example152E. ¹H NMR (500 MHz, CDCl₃): δ 1.46 (s, 9H) 1.53-1.74 (m, 4H) 2.43 (s,3H) 2.87 (d, J=11.55 Hz, 2H) 3.02 (s, 3H) 3.36-3.45 (m, 2H) 4.12-4.31(m, 4H) 4.85 (t, J=4.12 Hz, 1H) 7.16 (d, J=4.40 Hz, 1H) 7.55-7.64 (m,1H) 7.68 (d, J=8.80 Hz, 1H) 8.94 (t, J=8.25 Hz, 1H). LRMS (ESI): 522.2[M+H]⁺.

Example 153 iso-Propyl4-(4-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-methyl-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 153 was prepared from Example 152 using the methods described inExamples 8A and 8. ¹H NMR (500 MHz, CDCl₃): δ 1.17-1.30 (m, 6H)1.50-1.75 (m, 4H) 2.44 (s, 3H) 2.89 (s, 2H) 3.02 (s, 3H) 3.35-3.46 (m,2H) 4.12-4.38 (m, 4H) 4.82-4.97 (m, 2H) 7.16 (d, J=4.39 Hz, 1H) 7.61(dd, J=10.55, 2.20 Hz, 1H) 7.68 (dd, J=8.79, 2.64 Hz, 1H) 8.93 (t,J=8.35 Hz, 1H). LRMS (ESI): 508.2 [M+H]⁺.

Example 154 tert-Butyl4-(4-(2-chloro-4-(1H-imidazol-1-yl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 154A 2-Chloro-4-(1H-imidazol-1-yl)aniline

To 4-(1H-imidazol-1-yl)aniline (800 mg, 5.03 mmol) in DMF (5 ml) wasadded NCS (671 mg, 5.03 mmol), the reaction mixture was stirred at roomtemperature for 1 hour and then at 50° C. overnight and then at 100° C.overnight. The reaction was diluted with EtOAc, washed with water andbrine, dried over MgSO4 and concentrated in vacuo. The residue waspurified by a silica gel flash column and eluted by 0-40% EtOAc/Heane toafford Example 154A (121 mg, 0.625 mmol, 12.43% yield) as a light yellowsolid. ¹H NMR (500 MHz, CDCl₃): δ 4.31 (s, 2H) 6.79 (d, J=8.80 Hz, 1H)7.04 (dd, J=8.52, 2.47 Hz, 1H) 7.12 (d, J=3.85 Hz, 2H) 7.25 (t, J=3.02Hz, 1H) 7.68 (s, 1H). LRMS (ESI): 194.1 [M+H]⁺.

Example 154 tert-Butyl4-(4-(2-chloro-4-(1H-imidazol-1-yl)phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate

Example 154 was prepared from Example 3C using the same method describedabove for Example 3, with the exception that2-fluoro-4-(methylsulfonyl)aniline was replaced with2-chloro-4-(1H-imidazol-1-yl)aniline from Example 154A. ¹H NMR (400 MHz,CDCl₃): δ 1.39 (s, 9H) 1.50-1.57 (m, 2H) 1.58-1.66 (m, 2H) 2.80 (s, 2H)3.35-3.42 (m, 2H) 4.08-4.25 (m, 4H) 4.68-4.82 (m, 1H) 7.12 (d, J=8.79Hz, 2H) 7.17-7.21 (m, 1H) 7.25 (s, 1H) 7.33 (d, J=2.20 Hz, 1H) 7.71 (s,1H) 7.98 (s, 1H) 8.68 (d, J=8.79 Hz, 1H). LRMS (ESI): 512.3 [M+H]⁺.

Examples of Data

Data relevant to the range of activity for compounds of the presentinvention includes the following data in Table 1.

TABLE 1 Example hEC₅₀ No. Structure nM IA 7

2.78 0.81 26

8.06 0.51 146

8.52 0.88 143

9.74 0.41 89

10.28 0.65 55

11.08 0.72 145

11.36 0.87 154

12.92 0.65 45

158.20 0.63 47

162.70 0.78 134

163.50 0.59 118

179.40 0.63 120

181.10 0.45 15

188.40 0.48 49

196.50 0.67 18

198.00 0.46 76

3392.00 0.38 132

3401.00 0.37 100

3454.00 0.53 128

3587.00 0.7 69

4308.00 0.35 25

4518.00 0.27 127

6176.00 0.52 72

8581.00 0.34

What is claimed is:
 1. A compound of Formula I

and enantiomers, diastereomers and pharmaceutically acceptable saltsthereof wherein: A, B and D are each independently selected to beCR_(4b) or N; E is CH₂, O or NH, provided that when E is CH₂ at leastone of A, B or D is N; G is CH or N; Y is —NR₃, O or S; Z is absent or═O; n₁ is 1 or 2; n₂ and n₃ are each independently selected to be 0-2;n₄ is 0-3; R₁ is aryl or heteroaryl, each of which may optionally besubstituted with one or more substituents selected from R₄; R₂ isselected from the group consisting of cycloalkyl, aryl, heteroaryl,heterocyclyl, —C(═O)R₅ and —C(═O)OR₅, wherein the cycloalkyl, aryl,heteroaryl and heterocyclyl may each be optionally substituted with oneor more R₆'s; R₃ is selected from the group consisting of hydrogen,alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl; R₄, at each occurrence, isindependently selected from the group consisting of alkyl, aryl,alkenyl, alkynyl, cycloalkyl, heteroaryl, heterocyclyl, halo, —CN,—C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —S(O)₃H, —P(O)₃H₂,—C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉,—S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀,—NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀, —OC(═O)NR₉R₉, —C(═NR₁₄)NR₉R₉,—NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈ and —NR₉S(O₂)R₈,wherein the alkyl, aryl, alkenyl, alkynyl, cycloalkyl, heteroaryl andheterocyclyl may each be optionally substituted with one or more R₆'s;R_(4b), at each occurrence, is independently selected from the groupconsisting of hydrogen, alkyl, haloalkyl, aryl, alkenyl, alkynyl,cycloalkyl, heteroaryl, heterocyclyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH,—C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —S(O)₃H, —P(O)₃H₂,—C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉,—S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀,—NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀, —OC(═O)NR₉R₉, —C(═NR₁₄)NR₉R₉,—NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈ and —NR₉S(O₂)R₈,wherein the alkyl, aryl, alkenyl, alkynyl, cycloalkyl, heteroaryl andheterocyclyl may each be optionally substituted with one or more R₆'s;R₅ is selected from the group consisting of alkyl, aryl, cycloalkyl,heteroaryl and heterocyclyl, each of which may optionally be substitutedwith one or more R₆'s; R₆, at each occurrence, is independently selectedfrom the group consisting of alkyl, haloalkyl, aryl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclylheterocyclylalkyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OCF₃,—OR₁₀, —OH, —SH, —SR₁₀, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)H,—NR₉C(═O)R₁₀, —OC(═O)R₁₀, —C(═NR₁₄)NR₉R₉, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀,—S(O)₂R₁₀, —NR₉C(═O)OR₈ and —NR₉S(O₂)R₈; R₈, at each occurrence, isindependently selected from the group consisting of alkyl, aryl,cycloalkyl, heteroaryl and heterocyclyl; R₉, at each occurrence, isindependently selected from the group consisting of hydrogen, alkyl,alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl, wherein the aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl may eachbe optionally substituted with 0-5 R_(9a), and the heteroaryl,heteroarylalkyl, heterocyclyl and heterocyclylalkyl each contain 1-4heteroatoms selected from N, O and S; R_(9a), at each occurrence, isindependently selected from the group consisting of alkyl, haloalkyl,aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —NH₂, —CN, —NO₂,—C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —S(O)₃H, —P(O)₃H₂,—C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃,—C(═O)NR₁₄S(O)₂R₁₀, —S(O)₂NR₁₄C(═O)OR₁₀, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄,—C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)H, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄,—C(═NR₁₄)NR₁₄R₁₄, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄,—NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ and arylalkyl; R₁₀, at each occurrence, isindependently selected from the group consisting of alkyl, cycloalkyl,alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl, wherein the aryl, arylalkyl,heterocyclyl and heterocyclylalkyl may each be optionally substitutedwith 0-5 R_(10a), and the heterocyclyl and heterocyclylalkyl eachcontain 1-4 heteroatoms selected from N, O and S; R_(10a), at eachoccurrence, is independently selected from the group consisting ofalkyl, haloalkyl, aryl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl heterocyclylalkyl, halo, —NH₂,—CN, —NO₂, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄, —OH, —SH, —SR₁₄, —S(O)₃H,—P(O)₃H₂, —C(═O)NR₁₄R₁₄, —NR₁₄R₁₄, —S(O)₂NR₁₄R₁₄, —NR₁₄S(O)₂CF₃,—C(═O)NR₁₄S(O)₂R₉, —S(O)₂NR₁₄C(═O)OR₉, —S(O)₂NR₁₄C(═O)NR₁₄R₁₄,—C(═O)NR₁₄S(O)₂CF₃, —C(═O)R₁₄, —NR₁₄C(═O)H, —NR₁₄C(═O)R₁₄, —OC(═O)R₁₄,—C(═NR₁₄)NR₁₄R₁₄, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₄, —S(O)₂R₁₄,—NR₁₄C(═O)OR₈, —NR₁₄S(O₂)R₈ and arylalkyl; and R₁₄, at each occurrence,is independently selected from the group consisting of hydrogen, alkyl,cycloalkyl and aryl; excluding compounds wherein A and D are N orCR_(4b), B is CR_(4b), and E is O.
 2. A compound according to claim 1wherein A and D are each independently CR_(4b) or N, and B is CH.
 3. Acompound according to claim 2 wherein A and D are each independentlyCR_(4b) or N, B is CH, and E is NH.
 4. A compound according to claim 1selected from the group consisting of: a) compounds of claim 1 whereinA, B and D are each CR₄; b) compounds of claim 1 wherein A, B and D areeach CR_(4b), and E is NH; c) compounds of claim 1 wherein A and D areeach N, and B is CR_(4b); d) compounds of claim 1 wherein A is N, and Band D are each CR_(4b); and e) compounds of claim 1 wherein A is N, Band D are each CR_(4b), and E is NH.
 5. A compound according to claim 1wherein: Y is —NR₃, O or S; Z is absent or ═O; n₁ is 1 or 2; n₂ and n₃are each independently 1 or 2; n₄ is 0-3; R₁ is aryl or heteroaryl, eachof which may be optionally substituted with one or more substituentsselected from R₄; R₂ is selected from the group consisting ofcycloalkyl, aryl, heteroaryl, heterocyclyl, —C(═O)R₅ and —C(═O)OR₅,wherein the cycloalkyl, aryl, heteroaryl and heterocyclyl may each beoptionally substituted with one or more R₆'s; R₃ is hydrogen, alkyl orcycloalkyl; R₄, at each occurrence, is independently selected from thegroup consisting of C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6cycloalkyl, heteroaryl, heterocyclyl, halo, —CN, —C(═O)OH, —C(═O)OR₁₀,—OCF₃, —OH, —SH, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉,—NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀,—OC(═O)NR₉R₉, —C(═NR₁₄)NR₉R₉, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀,—NR₉C(═O)OR₈ and —NR₉S(O₂)R₈, wherein the alkyl, aryl, cycloalkyl,heteroaryl and heterocyclyl may each be optionally substituted with oneor more R₆'s; R_(4b), at each occurrence, is independently selected fromthe group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, halo,CN, —OH, —OR₁₀, —SR₁₀, aryl, heteroaryl and heterocyclyl, wherein thealkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl may each beoptionally substituted with one or more R₆'s; R₅ is alkyl, aryl,cycloalkyl, heteroaryl or heterocyclyl, each of which may be optionallysubstituted with one or more R₆'s; R₆, at each occurrence, isindependently selected from the group consisting of C1-6 alkyl, C1-4haloalkyl, C6-10 aryl, C3-6 cycloalkyl, heteroaryl, heterocyclyl, halo,—CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SH, —SR₁₀, —S(O)₃H,—P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃,—C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀,—C(═NR₁₄)NR₉R₉, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈and —NR₉S(O₂)R₈; R₈, at each occurrence, is independently selected fromthe group consisting of alkyl, aryl, cycloalkyl, heteroaryl andheterocyclyl; R₉, at each occurrence, is independently selected from thegroup consisting of hydrogen, C1-6 alkyl, C6-10 aryl, C3-6 cycloalkyl,heteroaryl and heterocyclyl, wherein the aryl, heteroaryl andheterocyclyl may each be optionally substituted with 0-5 R_(9a), and theheteroaryl and heterocyclyl each contain 1-4 heteroatoms selected fromN, O and S; R_(9a), at each occurrence, is independently selected fromthe group consisting of C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6cycloalkyl, heteroaryl, heterocyclyl, halo, —NH₂, —CN, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₄ and —OH; R₁₀, at each occurrence, isindependently selected from the group consisting of alkyl, cycloalkyl,aryl, heteroaryl and heterocyclyl, wherein the aryl, heteroaryl andheterocyclyl may be each optionally substituted with 0-5 R_(10a), andthe heteroaryl and heterocyclyl each contain 1-4 heteroatoms selectedfrom N, O and S; R_(10a), at each occurrence, is independently selectedfrom the group consisting of C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl,C3-6 cycloalkyl, heteroaryl, heterocyclyl, halo, —NH₂, —CN, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₄ and —OH; and R₁₄, at each occurrence, isindependently selected from the group consisting of hydrogen, C1-6alkyl, C3-6 cycloalkyl and C6-10 aryl.
 6. A compound according to claim1 wherein: Y is —NR₃, O or S; Z is absent or ═O; n₁ is 1 or 2; n₂ and n₃are each independently 1 or 2; n₄ is 0-3; R₁ is aryl or heteroaryl, eachof which may be optionally substituted with one or more substituentsselected from R₄; R₂ is aryl, heteroaryl, heterocyclyl, —C(═O)R₅ or—C(═O)OR₅, wherein the aryl, heteroaryl and heterocyclyl may each beoptionally substituted with one or more R₆'s; R₃ is hydrogen or alkyl;R₄, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6 cycloalkyl,heteroaryl, heterocyclyl, halo, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀,—OH, —SR₁₀, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉,—NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀,—OC(═O)NR₉R₉, —C(═NR₁₄)NR₉R₉, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀,—NR₉C(═O)OR₈ and —NR₉S(O₂)R₈, wherein the alkyl, aryl, cycloalkyl,heteroaryl and heterocyclyl may each be optionally substituted with oneor more R₆'s; R_(4b), at each occurrence, is independently selected fromthe group consisting of hydrogen, C1-6 alkyl, C1-4 haloalkyl, C6-10aryl, C3-6 cycloalkyl, halo, CN, —OH, —OR₁₀ and —SR₁₀, wherein thealkyl, cycloalkyl and aryl may each be optionally substituted with oneor more R₆'s; R₅ is selected from the group consisting of C1-6 alkyl,C6-10 aryl, C3-6 cycloalkyl, heteroaryl and heterocyclyl, each of whichmay be optionally substituted with one or more R₆'s; R₆, at eachoccurrence, is independently selected from the group consisting of C1-6alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6 cycloalkyl, heteroaryl,heterocyclyl, halo, —NH₂, —CN, —NO₂, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀,—OH, —SH, —SR₁₀, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉,—NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀,—C(═NR₁₄)NR₉R₉, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈and —NR₉S(O₂)R₈; R₈, at each occurrence, is independently selected fromthe group consisting of C1-6 alkyl, C6-10 aryl, C3-6 cycloalkyl,heteroaryl and heterocyclyl; R₉, at each occurrence, is independentlyselected from the group consisting of hydrogen, C1-6 alkyl, C6-10 aryl,C3-6 cycloalkyl, heteroaryl and heterocyclyl, wherein the aryl,heteroaryl and heterocyclyl may each be optionally substituted with 0-5R_(9a), and the heteroaryl and heterocyclyl each contain 1-4 heteroatomsselected from N, O and S; R_(9a), at each occurrence, is independentlyselected from the group consisting of C1-6 alkyl, halo, —NH₂, —CN,—C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄ and —OH; R₁₀, at each occurrence, isindependently selected from the group consisting of C1-6 alkyl, C3-6cycloalkyl, C6-10 aryl, heteroaryl and heterocyclyl, wherein the aryl,heteroaryl and heterocyclyl may each be optionally substituted with 0-5R_(10a), and the heteroaryl and heterocyclyl each contains 1-4heteroatoms selected from N, O and S; R_(10a), at each occurrence, isindependently selected from the group consisting of C1-6 alkyl, halo,—NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄ and —OH; and R₁₄, at eachoccurrence, is independently selected from the group consisting ofhydrogen, C1-6 alkyl and C6-10 aryl
 7. A compound according to claim 1wherein: Y is —NR₃, O or S; Z is absent or ═O; n₁ is 1 or 2; n₂ and n₃are independently 1 or 2; n₄ is 0 or 2; R₁ is C6-10 aryl or heteroaryl,each of which may be optionally substituted with one or moresubstituents selected from R₄; R₂ is C6-10 aryl, heteroaryl, —C(═O)R₅ or—C(═O)OR₅, wherein the aryl and heteroaryl may each be optionallysubstituted with one or more R₆'s; R₃ is hydrogen or C1-4 alkyl; R₄, ateach occurrence, is independently selected from the group consisting ofC1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6 cycloalkyl, heteroaryl,heterocyclyl, halo, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SR₁₀,—S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃,—C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀,—OC(═O)NR₉R₉, —C(═NR₁₄)NR₉R₉, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀,—NR₉C(═O)OR₈ and —NR₉S(O₂)R₈, wherein the alkyl, aryl, cycloalkyl,heteroaryl and heterocyclyl may each be optionally substituted with oneor more R₆'s; R_(4b), at each occurrence, is independently selected fromthe group consisting of hydrogen, C1-6 alkyl, C1-4 haloalkyl, C6-10aryl, C3-6 cycloalkyl, halo, CN, —OH, —OR₁₀ and —SR₁₀, wherein thealkyl, cycloalkyl and aryl may each be optionally substituted with oneor more R₆'s; R₅ is C1-6 alkyl, C6-10 aryl, C3-6 cycloalkyl orheteroaryl each of which may be optionally substituted with one or moreR₆'s; R₆, at each occurrence, is independently selected from the groupconsisting of C1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6 cycloalkyl,heteroaryl, heterocyclyl, halo, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀,—OH, —SR₁₀, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉,—NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉,—C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀,—C(═NR₁₄)NR₉R₉, —NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈and —NR₉S(O₂)R₈; R₈, at each occurrence, is independently selected fromthe group consisting of C1-6 alkyl, C6-10 aryl, C3-6 cycloalkyl andheteroaryl; R₉, at each occurrence, is independently selected from thegroup consisting of hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryland heteroaryl, wherein the aryl and heteroaryl may each be optionallysubstituted with 0-5 R_(9a), and the heteroaryl contains 1-4 heteroatomsselected from N, O and S; R_(9a), at each occurrence, is independentlyselected from the group consisting of C1-6 alkyl, halo, —NH₂, —CN,—C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄ and —OH; R₁₀, at each occurrence, isindependently selected from the group consisting of hydrogen, C1-6alkyl, C3-6 cycloalkyl, C6-10 aryl and heteroaryl, wherein the aryl andheteroaryl may each be optionally substituted with 0-5 R_(10a), and theheteroaryl contains 1-4 heteroatoms selected from N, O and S; R_(10a),at each occurrence, is independently selected from the group consistingof C1-6 alkyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄ and—OH; and R₁₄, at each occurrence, is independently selected from thegroup consisting of hydrogen, C1-6 alkyl and C6-10 aryl.
 8. A compoundaccording to claim 1 wherein: Y is —NR₃, O or S; Z is absent or ═O; n₁is 1 or 2; n₂ and n₃ are independently 1 or 2; n₄ is 0 or 2; R₁ is C6-10aryl or heteroaryl, each of which may be optionally substituted with oneor more substituents selected from R₄; R₂ is heteroaryl, —C(═O)R₅ or—C(═O)OR₅, wherein the heteroaryl may be optionally substituted with oneor more R₆'s; R₃ is hydrogen; R₄, at each occurrence, is independentlyselected from the group consisting of C1-6 alkyl, C1-4 haloalkyl, C6-10aryl, C3-6 cycloalkyl, heteroaryl, heterocyclyl, halo, —CN, —C(═O)OH,—C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SR₁₀, —S(O)₃H, —P(O)₃H₂, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀, —NR₉C(═O)H,—NR₉C(═O)R₁₀, —OC(═O)R₁₀, —OC(═O)NR₉R₉, —C(═NR₁₄)NR₉R₉,—NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈ and —NR₉S(O₂)R₈,wherein the alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl mayeach be optionally substituted with one or more R₆'s; R_(4b), at eachoccurrence, is independently selected from the group consisting ofhydrogen, C1-6 alkyl, C6-10 aryl and C3-6 cycloalkyl, wherein the alkyl,cycloalkyl, and aryl may each be optionally substituted with one or moreR₆'s; R₅ is C1-6 alkyl, C6-10 aryl or C3-6 cycloalkyl, each of which maybe optionally substituted with one or more R₆'s; R₆, at each occurrence,is independently selected from the group consisting of C1-6 alkyl, C1-4haloalkyl, C6-10 aryl, C3-6 cycloalkyl, heteroaryl, heterocyclyl, halo,—CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SR₁₀, —S(O)₃H, —P(O)₃H₂,—C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —NR₉S(O)₂CF₃, —C(═O)NR₉S(O)₂R₉,—S(O)₂NR₉C(═O)OR₉, —S(O)₂NR₉C(═O)NR₉R₉, —C(═O)NR₉S(O)₂CF₃, —C(═O)R₁₀,—NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)R₁₀, —C(═NR₁₄)NR₉R₉,—NHC(═NR₁₄)NR₁₄R₁₄, —S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈ and —NR₉S(O₂)R₈;R₈, at each occurrence, is independently C1-6 alkyl or C6-10 aryl; R₉,at each occurrence, is independently hydrogen, C1-6 alkyl, C3-6cycloalkyl, C6-10 aryl or heteroaryl, wherein the aryl and heteroarylmay each be optionally substituted with 0-5 R_(9a), and the heteroarylcontains 1-4 heteroatoms selected from N, O and S; R_(9a), at eachoccurrence, is independently selected from the group consisting of C1-6alkyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄ and —OH; R₁₀,at each occurrence, is independently selected from the group consistingof hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C6-10 aryl and heteroaryl,wherein the aryl and heteroaryl may each be optionally substituted with0-5 R_(10a), and the heteroaryl contains 1-4 heteroatoms selected fromN, O and S; R_(10a), at each occurrence, is independently selected fromthe group consisting of C1-6 alkyl, halo, —NH₂, —CN, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₄ and —OH; and R₁₄, at each occurrence, isindependently selected from the group consisting of hydrogen, C1-6 alkyland C6-10 aryl.
 9. A compound according to claim 1 wherein: Y is —NR₃, Oor S; Z is absent or ═O; n₁ is 1 or 2; n₂ and n₃ are independently 1 or2; n₄ is 0; R₁ is C6-10 aryl or heteroaryl, each of which may beoptionally substituted with one or more substituents selected from R₄;R₂ is heteroaryl, —C(═O)R₅ or —C(═O)OR₅, wherein the heteroaryl may beoptionally substituted with one or more R₆'s; R₃ is hydrogen; R₄, ateach occurrence, is independently selected from the group consisting ofC1-6 alkyl, C1-4 haloalkyl, C6-10 aryl, C3-6 cycloalkyl, heteroaryl,heterocyclyl, halo, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SR₁₀,—C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉,—C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)NR₉R₉, —S(═O)R₁₀, —S(O)₂R₁₀,—NR₉C(═O)OR₈ and —NR₉S(O₂)R₈, wherein the alkyl, aryl, cycloalkyl,heteroaryl and heterocyclyl may each be optionally substituted with oneor more R₆'s; R_(4b), at each occurrence, is independently selected fromthe group consisting of hydrogen, C1-6 alkyl and C3-6 cycloalkyl,wherein the alkyl and cycloalkyl may each be optionally substituted withone or more R₆'s; R₅ is C1-6 alkyl, C6-10 aryl or C3-6 cycloalkyl, eachof which may be optionally substituted with one or more R₆'s; R₆, ateach occurrence, is independently selected from the group consisting ofC1-6 alkyl, C6-10 aryl, C3-6 cycloalkyl, heteroaryl, heterocyclyl, halo,—CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SR₁₀, —C(═O)NR₉R₉,—NR₉R₉, —S(O)₂NR₉R₉, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —C(═O)R₁₀,—NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)NR₉R₉, —S(═O)R₁₀, —S(O)₂R₁₀,—NR₉C(═O)OR₈ and —NR₉S(O₂)R₈; R₈, at each occurrence, is independentlyC1-6 alkyl or C6-10 aryl; R₉, at each occurrence, is independentlyhydrogen, C1-6 alkyl, C3-6 cycloalkyl or C6-10 aryl, wherein the arylmay be optionally substituted with 0-5 R_(9a); R_(9a), at eachoccurrence, is independently selected from the group consisting of C1-6alkyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄ and —OH; R₁₀,at each occurrence, is independently hydrogen, C1-6 alkyl, C3-6cycloalkyl or C6-10 aryl, wherein the aryl may be optionally substitutedwith 0-5 R_(10a); R_(10a), at each occurrence, is independently selectedfrom the group consisting of C1-6 alkyl, halo, —NH₂, —CN, —C(═O)OH,—C(═O)OR₁₄, —OCF₃, —OR₁₄ and —OH; and R₁₄, at each occurrence, isindependently selected from the group consisting of hydrogen, C1-6 alkyland C6-10 aryl.
 10. A compound according to claim 1 wherein: A and D areindependently CH or N; B is CH; G is CH or N; Y is —NR₃ or O; Z isabsent or ═O; n₁ is 1 or 2; n₂ and n₃ are 1; n₄ is 0; R₁ is phenyl orheteroaryl, each of which may be optionally substituted with 1-5 of R₄;R₂ is heteroaryl, —C(═O)R₅ or —C(═O)OR₅, wherein the heteroaryl may beoptionally substituted with 1-5 of R₆'s; R₃ is hydrogen; R₄, at eachoccurrence, is independently selected from the group consisting of C1-6alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, phenyl, heteroaryl, halo, —CN,—C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉,—S(O)₂NR₉R₉, —C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —C(═O)R₁₀, —NR₉C(═O)H,—NR₉C(═O)R₁₀, —OC(═O)NR₉R₉, —S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈ and—NR₉S(O₂)R₈, wherein the alkyl, phenyl and heteroaryl may each beoptionally substituted 1-5 of R₆'s; R_(4b), at each occurrence, isindependently selected from hydrogen and C1-6 alkyl; R₅ is C1-6 alkyl,C3-6 cycloalkyl or phenyl, each of which may be optionally substitutedwith 1-5 of R₆'s; R₆, at each occurrence, is independently selected fromthe group consisting of C1-6 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl,phenyl, heteroaryl, halo, —CN, —C(═O)OH, —C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH,—SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉, —C(═O)NR₉S(O)₂R₉,—S(O)₂NR₉C(═O)OR₉, —C(═O)R₁₀, —NR₉C(═O)H, —NR₉C(═O)R₁₀, —OC(═O)NR₉R₉,—S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈ and —NR₉S(O₂)R₈; R₈, at eachoccurrence, is independently C1-6 alkyl or phenyl; R₉, at eachoccurrence, is independently hydrogen, C1-6 alkyl, C3-6 cycloalkyl orphenyl, wherein the phenyl may be optionally substituted with 0-5R_(9a); R_(9a), at each occurrence, is independently selected from thegroup consisting of C1-6 alkyl, halo, —NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄,—OCF₃, —OR₁₄ and —OH; R₁₀, at each occurrence, is independentlyhydrogen, C1-6 alkyl, C3-6 cycloalkyl or phenyl, wherein the phenyl maybe optionally substituted with 0-5 R_(10a); R_(10a), at each occurrence,is independently selected from the group consisting of C1-6 alkyl, halo,—NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄ and —OH; and R₁₄, at eachoccurrence, is independently selected from the group consisting ofhydrogen, C1-6 alkyl and phenyl.
 11. A compound according to claim 1wherein: A and D are independently CH or N; B is CH; G is N; Y is —NR₃or O; Z is absent or ═O; n₁ is 1 or 2; n₂ and n₃ are 1; n₄ is 0; R₁ isphenyl, pyridyl or pyrimidinyl, each of which may be optionallysubstituted with 1-5 of R₄; R₂ is —C(═O)OR₅ or a heteroaryl selectedfrom the group consisting of pyrimidinyl, pyridyl, oxadiazolyl andbenzoxazole, wherein the heteroaryl may be optionally substituted with1-5 of R₆'s; R₃ is hydrogen; R₄, at each occurrence, is independentlyselected from the group consisting of C1-6 alkyl, C1-4 haloalkyl, C3-6cycloalkyl, phenyl, heteroaryl which has a single ring with 6 atoms ofwhich 1-3 are selected from O, S and N, halo, —CN, —C(═O)OH, —C(═O)OR₁₀,—OCF₃, —OR₁₀, —OH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉,—C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —C(═O)R₁₀, —NR₉C(═O)H,—NR₉C(═O)R₁₀, —OC(═O)NR₉R₉, —S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈ and—NR₉S(O₂)R₈, wherein the alkyl, phenyl and heteroaryl may each beoptionally substituted with 1-5 of R₆'s; R_(4b), at each occurrence, ishydrogen; R₅ is C1-6 alkyl, C3-6 cycloalkyl or phenyl, each of which maybe optionally substituted with 1-5 of R₆'s; R₆, at each occurrence, isindependently selected from the group consisting of C1-6 alkyl, C1-4haloalkyl, C3-6 cycloalkyl, phenyl, heteroaryl, halo, —CN, —C(═O)OH,—C(═O)OR₁₀, —OCF₃, —OR₁₀, —OH, —SR₁₀, —C(═O)NR₉R₉, —NR₉R₉, —S(O)₂NR₉R₉,—C(═O)NR₉S(O)₂R₉, —S(O)₂NR₉C(═O)OR₉, —C(═O)R₁₀, —NR₉C(═O)H,—NR₉C(═O)R₁₀, —OC(═O)NR₉R₉, —S(═O)R₁₀, —S(O)₂R₁₀, —NR₉C(═O)OR₈ and—NR₉S(O₂)R₈; R₈, at each occurrence, is independently C1-6 alkyl orphenyl; R₉, at each occurrence, is independently hydrogen, C1-6 alkyl,C3-6 cycloalkyl or phenyl, wherein the phenyl may be optionallysubstituted with 0-5 R_(9a); R_(9a), at each occurrence, isindependently selected from the group consisting of C1-6 alkyl, halo,—NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄ and —OH; R₁₀, at eachoccurrence, is independently selected from the group consisting of C1-6alkyl, C3-6 cycloalkyl and phenyl, wherein the phenyl may be optionallysubstituted with 0-5 R_(10a); R_(10a), at each occurrence, isindependently selected from the group consisting of C1-6 alkyl, halo,—NH₂, —CN, —C(═O)OH, —C(═O)OR₁₄, —OCF₃, —OR₁₄ and —OH; and R₁₄, at eachoccurrence, is independently selected from the group consisting ofhydrogen and C1-6 alkyl.
 12. A compound according to claim 11 wherein Aand D each are N.
 13. A compound according to claim 1 selected from thegroup consisting of:


14. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim
 1. 15. The pharmaceutical composition ofclaim 14 further comprising a pharmaceutically acceptable carrier. 16.The pharmaceutical composition of claim 14 further comprising at leastone additional therapeutically active agent.
 17. The pharmaceuticalcomposition of claim 16, wherein the additional therapeutically activeagent is a glucagon-like peptide-1 receptor agonist or fragment thereof.18. A method of modulating the activity of the GPR119 G protein-coupledreceptor comprising administering to a mammalian patient in need thereofa therapeutically effective amount of at least one compound of claim 1and, optionally, at least one other therapeutic agent.
 19. The method ofclaim 18, wherein diseases or disorders associated with modulating theactivity of the GPR119 G protein-coupled receptor that can be preventedor treated is selected from the group consisting of diabetes,hyperglycemia, impaired glucose tolerance, insulin resistance,hyperinsulinemia, retinopathy, neuropathy, nephropathy, delayed woundhealing, atherosclerosis and its sequelae, abnormal heart function,myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity,dislipidemia, dylsipidemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low HDL, high LDL, non-cardiac ischemia,infection, cancer, vascular restenosis, pancreatitis, neurodegenerativedisease, lipid disorders, cognitive impairment and dementia, bonedisease, HIV protease associated lipodystrophy and glaucoma.
 20. Amethod for preventing, modulating, or treating the progression or onsetof a disease or condition selected from the group consisting ofdiabetes, hyperglycemia, obesity, dyslipidemia, hypertension andcognitive impairment comprising administering to a mammalian patient, inneed of said prevention, modulation, or treatment a therapeuticallyeffective amount of a compound of claim 1, and optionally, atherapeutically effective amount of an additional therapeutic agent.